Potent dual brd4-kinase inhibitors as cancer therapeutics

ABSTRACT

Disclosed herein are compounds that are inhibitors of BRD4 and their use in the treatment of cancer. Methods of screening for selective inhibitors of BRD4 are also disclosed. In certain aspects, disclosed are compounds of Formula I-IV.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/032,619, filed Aug. 3, 2014, 62/032,884, filed Aug.4, 2014, 62/057,607, filed Sep. 30, 2015, 62/149,860, filed Apr. 20,2015, and 62/197,053, filed Jul. 26, 2015, the disclosures of which areeach incorporated by reference herein in their entireties.

STATEMENT REGARDING GOVERNMENT SUPPORT

This invention was made with government support under grant no.HHSN275201300017C awarded by the National Institute of Child Health andHuman Development. The government has certain rights in this invention.

FIELD

The subject matter disclosed herein relates generally to cancer therapyand to anti-cancer compounds. More specifically, the subject matterdisclosed herein relates to inhibitors of BRD4 and their use in thetreatment of cancer. Methods of screening for selective inhibitors ofBRD4 are also disclosed.

BACKGROUND

Bromodomain (BRD)-containing proteins are essential for the recognitionof acetylated lysine (KAc) residues of histones during transcriptionalactivation (Sanchez et al., The role of human bromodomains in chromatinbiology and gene transcription. Current opinion in drug discovery &development 2009, 12, 659-65). BRDs have emerged as promising drugtargets for a number of disease pathways that are characterized bychanges in the epigenetic cell signature (Id.; Filippakopoulos et al.,Selective inhibition of BET bromodomains. Nature 2010, 468, 1067-731).To date, only a few structurally diverse BRD inhibitors have beenreported, all of which specifically target the KAc recognition sites ofthe bromodomain and extra terminal (BET) family of proteins (BRD2, BRD3,BRD4, and BRDT), each containing two tandem BRDs (Hewings et al.,Progress in the development and application of small molecule inhibitorsof bromodomain-acetyl-lysinc interactions. J Med Chem 2012, 55,9393-413; Muller et al., Bromodomains as therapeutic targets. Expert RevMol Med 2011, 13, e29; Prinjha et al., Place your BETs: the therapeuticpotential of bromodomains. Trends Pharmacol Sci 2012, 33, 146-53).BET-inhibitors exert a broad spectrum of desirable biological effectssuch as anticancer and anti-inflammatory properties (Delmore et al., BETbromodomain inhibition as a therapeutic strategy to target c-Myc. Cell2011, 146, 904-17; Matzuk et al., Small-Molecule Inhibition of BRDT forMale Contraception. Cell 2012, 150, 673-684; Mertz et al., Targeting MYCdependence in cancer by inhibiting BET bromodomains. Proc Nat Acad SciUSA 2011, 108, 16669-74; Ott et al., BET bromodomain inhibition targetsboth c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood2012, 120, 2843-52; Puissant et al., Targeting MYCN in neuroblastoma byBET bromodomain inhibition. Cancer Discov 2013, 3, 308-23). Of these,I-BET-762 (GSK525762) has recently entered clinical trials for thetreatment of NUT midline carcinoma (Mirguet et al., Discovery ofepigenetic regulator I-BET762: lead optimization to afford a clinicalcandidate inhibitor of the BET bromodomains. J Med Chem 2013, 56,7501-15). Intense efforts are currently underway to discover newchemical scaffolds for hit-to-lead development campaigns of BETinhibitors as novel therapeutics (Filippakopoulos et al.,Benzodiazepines and benzotriazepines as protein interaction inhibitorstargeting bromodomains of the BET family. Bioorg Med Chem 2012, 20,1878-86; Fish et al., Identification of a chemical probe for bromo andextra C-terminal bromodomain inhibition through optimization of afragment-derived hit. J Med Chem 2012, 55, 9831-7; Mirguet et al.,Naphthyridines as Novel BET Family Bromodomain Inhibitors. Chem Med Chem2014, 9, 580-9; Seal et al., Identification of a novel series of BETfamily bromodomain inhibitors: binding mode and profile of I-BET151(GSK1210151A). Bioorg & Med Chem Lett 2012, 22, 2968-72).

Recently, it was discovered that BETs interact with diverse kinaseinhibitors (Martin et al., Cyclin-dependent kinase inhibitor dinaciclibinteracts with the acetyl-lysine recognition site of bromodomains. ChemBiol 2013, 8, 2360; Ember et al., The acetyl-lysine binding site ofbromodomain-containing protein 4 (BRD4) interacts with diverse kinaseinhibitors. Chem Biol 2014; Ciceri et al., Dual kinase-bromodomaininhibitors for rationally designed polypharmacology. Nat Chem Biol2014). Among these, the PLK1 inhibitor BI2536 and the JAK2/FLT3inhibitors TG101348 and TG101209 inhibited the binding of KAc peptide toBRD4 with IC₅₀ values of 0.03 and 0.13 μM, respectively, and showedstrong downregulation of c-Myc in MM.1S cells. These activities weresimilar to that of the prototypic BET inhibitor JQ1, the most potentBRD4 inhibitor described to date. Furthermore, TG101348, but not JAK2inhibitors that lack BET and FLT3 activity, potently inhibitedproliferation of MV4-11 AML cells (IC₅₀=79 nM)(Id.). AML is often drivenby BETs and mutant FLT38 (Smith et al., Validation of ITD mutations inFLT3 as a therapeutic target in human acute myeloid leukaemia. Nature2012, 485, 260-3) and the findings by Knapp and colleagues providedcompelling evidence of an oncology indication that could be exploitedthrough dual targeting of kinases and bromodomains. Thus there is a needfor new compositions and methods that target both kinases andbromodomains. The compositions and methods disclosed herein addressthese and other needs.

SUMMARY

In accordance with the purposes of the disclosed materials and methods,as embodied and broadly described herein, the disclosed subject matter,in one aspect, relates to compounds, compositions and methods of makingand using compounds and compositions. In specific aspects, the disclosedsubject matter relates to cancer therapy and to anti-cancer compounds.More specifically, the subject matter disclosed herein relates toinhibitors of BET and kinases. In more specific examples, the disclosedsubject matter relates to inhibitors of BRD4 and their use in thetreatment of cancer. Methods of screening for new BRD4 inhibitors arealso disclosed.

Additional advantages will be set forth in part in the description thatfollows, and in part will be obvious from the description, or may belearned by practice of the aspects described below. The advantagesdescribed below will be realized and attained by means of the elementsand combinations particularly pointed out in the appended claims. It isto be understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects described below.

FIG. 1 shows SAR studies of analogues of TG101209. MM1.S cells wereexposed for 6 hours to compounds that showed sub-micromolar bindingpotential for BRD4 by DSF. Cellular levels of pSTAT3 (JAK2 activity) andc-Myc (BRD4 activity) were determined by Western blotting. IC₅₀ valuesfor cell survival were determined by MTT assay after 72 hours compoundexposure. Increased anti-proliferative effects are correlated with anearly, strong reduction of both pSTAT2 and c-Myc levels. The inhibitorshighlighted are the most promising equipotent dual BET-JAK2 inhibitorsof this series. JQ1 and the BET-inactive JAK2 inhibitor NVP-BSK805served as controls.

FIG. 2 shows the activity of several compounds disclosed herein invarious cancer cell lines.

DETAILED DESCRIPTION

The materials, compounds, compositions, and methods described herein maybe understood more readily by reference to the following detaileddescription of specific aspects of the disclosed subject matter, theFigures, and the Examples included therein.

Before the present materials, compounds, compositions, and methods aredisclosed and described, it is to be understood that the aspectsdescribed below are not limited to specific synthetic methods orspecific reagents, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular aspects only and is not intended to be limiting.

Also, throughout this specification, various publications arereferenced. The disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which the disclosed matterpertains. The references disclosed are also individually andspecifically incorporated by reference herein for the material containedin them that is discussed in the sentence in which the reference isrelied upon.

General Definitions

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

Throughout the specification and claims the word “comprise” and otherforms of the word, such as “comprising” and “comprises,” means includingbut not limited to, and is not intended to exclude, for example, otheradditives, components, integers, or steps.

As used in the description and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a composition”includes mixtures of two or more such compositions, reference to “aninhibitor” includes mixtures of two or more such inhibitors, referenceto “the kinase” includes mixtures of two or more such kinase, and thelike.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the disclosure are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Furthermore, when numerical ranges ofvarying scope are set forth herein, it is contemplated that anycombination of these values inclusive of the recited values may be used.Further, ranges can be expressed herein as from “about” one particularvalue, and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. Unless stated otherwise, the term “about” means within 5%(e.g., within 2% or 1%) of the particular value modified by the term“about.”

By “reduce” or other forms of the word, such as “reducing” or“reduction,” is meant lowering of an event or characteristic (e.g.,tumor growth, metastasis). It is understood that this is typically inrelation to some standard or expected value, in other words it isrelative, but that it is not always necessary for the standard orrelative value to be referred to. For example, “reduces tumor growth”means decreasing the amount of tumor cells relative to a standard or acontrol.

By “prevent” or other forms of the word, such as “preventing” or“prevention,” is meant to stop a particular event or characteristic, tostabilize or delay the development or progression of a particular eventor characteristic, or to minimize the chances that a particular event orcharacteristic will occur. Prevent does not require comparison to acontrol as it is typically more absolute than, for example, reduce. Asused herein, something could be reduced but not prevented, but somethingthat is reduced could also be prevented. Likewise, something could beprevented but not reduced, but something that is prevented could also bereduced. It is understood that where reduce or prevent are used, unlessspecifically indicated otherwise, the use of the other word is alsoexpressly disclosed.

As used herein, “treatment” refers to obtaining beneficial or desiredclinical results. Beneficial or desired clinical results include, butare not limited to, any one or more of: alleviation of one or moresymptoms (such as tumor growth or metastasis), diminishment of extent ofcancer, stabilized (i.e., not worsening) state of cancer, preventing ordelaying spread (e.g., metastasis) of the cancer, preventing or delayingoccurrence or recurrence of cancer, delay or slowing of cancerprogression, amelioration of the cancer state, and remission (whetherpartial or total).

The term “patient” preferably refers to a human in need of treatmentwith an anti-cancer agent or treatment for any purpose, and morepreferably a human in need of such a treatment to treat cancer, or aprecancerous condition or lesion. However, the term “patient” can alsorefer to non-human animals, preferably mammals such as dogs, cats,horses, cows, pigs, sheep and non-human primates, among others, that arein need of treatment with an anti-cancer agent or treatment.

It is understood that throughout this specification the identifiers“first” and “second” are used solely to aid in distinguishing thevarious components and steps of the disclosed subject matter. Theidentifiers “first” and “second” are not intended to imply anyparticular order, amount, preference, or importance to the components orsteps modified by these terms.

Chemical Definitions

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a mixture containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the mixture.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc.

The term “aliphatic” as used herein refers to a non-aromatic hydrocarbongroup and includes branched and unbranched, alkyl, alkenyl, or alkynylgroups.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl,tetracosyl, and the like. The alkyl group can also be substituted orunsubstituted. The alkyl group can be substituted with one or moregroups including, but not limited to, alkyl, halogenated alkyl, alkoxy,alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid,ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,sulfonyl, sulfone, sulfoxide, or thiol, as described below.

The symbols A^(n) is used herein as merely a generic substituent in thedefinitions below.

The term “alkoxy” as used herein is an alkyl group bound through asingle, terminal ether linkage; that is, an “alkoxy” group can bedefined as —O^(A) where A¹ is alkyl as defined above.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This may be presumedin structural formulae herein wherein an asymmetric alkene is present,or it may be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide,or thiol, as described below.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be substituted with oneor more groups including, but not limited to, alkyl, halogenated alkyl,alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylicacid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,sulfonyl, sulfone, sulfoxide, or thiol, as described below.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “heteroaryl” isdefined as a group that contains an aromatic group that has at least oneheteroatom incorporated within the ring of the aromatic group. Examplesof heteroatoms include, but are not limited to, nitrogen, oxygen,sulfur, and phosphorus. The term “non-heteroaryl,” which is included inthe term “aryl,” defines a group that contains an aromatic group thatdoes not contain a heteroatom. The aryl and heteroaryl group can besubstituted or unsubstituted. The aryl and heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol asdescribed herein. The term “biaryl” is a specific type of aryl group andis included in the definition of aryl. Biaryl refers to two aryl groupsthat are bound together via a fused ring structure, as in naphthalene,or are attached via one or more carbon-carbon bonds, as in biphenyl.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. The term “heterocycloalkyl” is a cycloalkyl group asdefined above where at least one of the carbon atoms of the ring issubstituted with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkylgroup can be substituted or unsubstituted. The cycloalkyl group andheterocycloalkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide,or thiol as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onedouble bound, i.e., C═C. Examples of cycloalkenyl groups include, butare not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term“heterocycloalkenyl” is a type of cycloalkenyl group as defined abovewhere at least one of the carbon atoms of the ring is substituted with aheteroatom such as, but not limited to, nitrogen, oxygen, sulfur, orphosphorus. The cycloalkenyl group and heterocycloalkenyl group can besubstituted or unsubstituted. The cycloalkenyl group andheterocycloalkenyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide,or thiol as described herein.

The term “cyclic group” is used herein to refer to either aryl groups,non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl groups), or both. Cyclic groups have one or more ringsystems that can be substituted or unsubstituted. A cyclic group cancontain one or more aryl groups, one or more non-aryl groups, or one ormore aryl groups and one or more non-aryl groups.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for C═O.

The terms “amine” or “amino” as used herein are represented by theformula NA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen,an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groupdescribed above.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH. A “carboxylate” as used herein is represented by the formula—C(O)O⁻.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be an alkyl, halogenated alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,or heterocycloalkenyl group described above.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, halogenated alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group described above.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, halogenated alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group described above.

The term “halide” as used herein refers to the halogens fluorine,chlorine, bromine, and iodine.

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “cyano” as used herein is represented by the formula —CN Theterm “azido” as used herein is represented by the formula —N₃.

The term “oxo” as used herein is represented by ═O.

The term “sulfonyl” is used herein to refer to the sulfo-oxo grouprepresented by the formula —S(O)₂A¹, where A¹ can be hydrogen, an alkyl,halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group describedabove. The term “sulfoxide” is used herein to refer to the sulfo-oxogroup represented by the formula —OS(O)₂A¹, where A¹ can be hydrogen, analkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groupdescribed above.

The term “sulfonylamino” or “sulfonamide” as used herein is representedby the formula —S(O)₂NH₂.

The term “thiol” as used herein is represented by the formula —SH.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R-) or (S-)configuration. The compounds provided herein may either beenantiomerically pure, or be diastereomeric or enantiomeric mixtures. Itis to be understood that the chiral centers of the compounds providedherein may undergo epimerization in vivo. As such, one of skill in theart will recognize that administration of a compound in its (R-) form isequivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S-) form.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), nuclearmagnetic resonance (NMR), gel electrophoresis, high performance liquidchromatography (HPLC) and mass spectrometry (MS), gas-chromatographymass spectrometry (GC-MS), and similar, used by those of skill in theart to assess such purity, or sufficiently pure such that furtherpurification would not detectably alter the physical and chemicalproperties, such as enzymatic and biological activities, of thesubstance. Both traditional and modern methods for purification of thecompounds to produce substantially chemically pure compounds are knownto those of skill in the art. A substantially chemically pure compoundmay, however, be a mixture of stereoisomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer, diastereomer, and meso compound,and a mixture of isomers, such as a racemic or scalemic mixture.

A “pharmaceutically acceptable” component is one that is suitable foruse with humans and/or animals without undue adverse side effects (suchas toxicity, irritation, and allergic response) commensurate with areasonable benefit/risk ratio.

“Pharmaceutically acceptable salt” refers to a salt that ispharmaceutically acceptable and has the desired pharmacologicalproperties. Such salts include those that may be formed where acidicprotons present in the compounds are capable of reacting with inorganicor organic bases. Suitable inorganic salts include those formed with thealkali metals, e.g., sodium, potassium, magnesium, calcium, andaluminum. Suitable organic salts include those formed with organic basessuch as the amine bases, e.g., ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, and the like. Suchsalts also include acid addition salts formed with inorganic acids(e.g., hydrochloric and hydrobromic acids) and organic acids (e.g.,acetic acid, citric acid, maleic acid, and the alkane- andarene-sulfonic acids such as methanesulfonic acid and benzenesulfonicacid). When two acidic groups are present, a pharmaceutically acceptablesalt may be a mono-acid-mono-salt or a di-salt; similarly, where thereare more than two acidic groups present, some or all of such groups canbe converted into salts.

“Pharmaceutically acceptable excipient” refers to an excipient that isconventionally useful in preparing a pharmaceutical composition that isgenerally safe, non-toxic, and desirable, and includes excipients thatare acceptable for veterinary use as well as for human pharmaceuticaluse. Such excipients can be solid, liquid, semisolid, or, in the case ofan aerosol composition, gaseous.

A “pharmaceutically acceptable carrier” is a carrier, such as a solvent,suspending agent or vehicle, for delivering the disclosed compounds tothe patient. The carrier can be liquid or solid and is selected with theplanned manner of administration in mind. Liposomes are also apharmaceutical carrier. As used herein, “carrier” includes any and allsolvents, dispersion media, vehicles, coatings, diluents, antibacterialand antifungal agents, isotonic and absorption delaying agents, buffers,carrier solutions, suspensions, colloids, and the like. The use of suchmedia and agents for pharmaceutical active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician. In reference to cancers or other unwanted cellproliferation, an effective amount comprises an amount sufficient tocause a tumor to shrink and/or to decrease the growth rate of the tumor(such as to suppress tumor growth) or to prevent or delay other unwantedcell proliferation. In some embodiments, an effective amount is anamount sufficient to delay development. In some embodiments, aneffective amount is an amount sufficient to prevent or delay occurrenceand/or recurrence. An effective amount can be administered in one ormore doses. In the case of cancer, the effective amount of the drug orcomposition may: (i) reduce the number of cancer cells; (ii) reducetumor size; (iii) inhibit, retard, slow to some extent and preferablystop cancer cell infiltration into peripheral organs; (iv) inhibit(i.e., slow to some extent and preferably stop) tumor metastasis; (v)inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrenceof tumor; and/or (vii) relieve to some extent one or more of thesymptoms associated with the cancer.

Effective amounts of a compound or composition described herein fortreating a mammalian subject can include about 0.1 to about 1000 mg/Kgof body weight of the subject/day, such as from about 1 to about 100mg/Kg/day, especially from about 10 to about 100 mg/Kg/day. The dosescan be acute or chronic. A broad range of disclosed composition dosagesare believed to be both safe and effective.

Reference will now be made in detail to specific aspects of thedisclosed materials, compounds, compositions, articles, and methods,examples of which are illustrated in the accompanying Examples andFigures.

Compounds

Disclosed are compounds that are BRD4 inhibitors. These disclosedcompounds can be used in various compositions as anti-cancertherapeutics.

In certain embodiments, the disclosed compounds have the chemicalstructure shown in Formula I.

wherein

-   -   R¹ is selected from the group consisting of H, Cl, F, Br, I, CN,        NO₂, NH₂, CF₃, CO₂H, CO₂NH₂, CO₂NHR⁵, CO₂R⁵, C(O)R⁵, C(O)NH₂,        C(O)NHR⁵, or C₁-C₆ alkyl optionally substituted with alkoxy,        alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic        acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,        sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   R² is H, OH, CN, NO₂, NH₂, unsubstituted C₁-C₆ alkyl,        cycloalkyl, aryl, or heteroaryl; or C₁-C₆ alkyl, cycloalkyl,        aryl, or heteroaryl substituted with alkoxy, alkenyl, alkynyl,        aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,        ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,        sulfonyl, sulfone, sulfoxide, or thiol;    -   or R¹ and R² together form a fused cycloalkyl, cycloheteroalkyl,        aryl or heteraryl group;    -   each R³ is selected, independently, from the group consisting of        SO₂NH₂, SO₂NHR⁵, NHSO₂R⁵, NHCO₂R⁵, NHC(O)R⁵, NHCONHR⁵, F, Cl,        Br, I, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloheteroaryl, and        fused cycloheteroalkyl, optionally substituted with sulfonyl;    -   each R⁴ is selected, independently, from the group consisting of        F, Cl, Br, I, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, COOH, C(O)NH₂,        C(O)R⁵, C(O)NHR⁵, CH₂C(O)R⁵, SO₂NH₂, SO₂NHR⁵, or CONHSO₂R⁵, or        phenyl, OPhenyl, tetrazole, piperadinyl, piperazinyl,        morpholinyl, optionally substituted with alkoxy, alkenyl,        alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid,        ester, ether, halide, hydroxy, ketone, nitro, oxo, silyl,        sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   each R⁵ is selected, independently, from C₁-C₆ alkyl, C₁-C₆        cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or heteroalkyl,        any of which are optionally substituted with C₁-C₆ alkyl, C₁-C₆        alkoxyl, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino,        carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro,        oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;        -   R⁷ is H, C₁-C₆ alkyl, C₁-C₆ alkoxyl, halide, hydroxyl,            cyano, nitro, or amino;    -   n is 1-5; and    -   m is 1-5    -   or a pharmaceutically acceptable salt thereof.        Thus, in the disclosed compounds there can be from 1 to 5        different substituents R³ and from 1 to 5 different substituents        R⁴. Pharmaceutically acceptable salts of these compounds a are        also disclosed. In one specific example, R¹ is methyl, R² is        hydrogen, R³ is SO₂NHtBu, and R⁴ is OCH₂CH₂pyrrol (TG101348)

In other examples, disclosed herein are compounds of Formula IIA.

-   -   wherein    -   X is CH or N;    -   R¹ is selected from the group consisting of H, Cl, F, Br, I, CN,        NO₂, NH₂, CF₃, CO₂H, CO₂NH₂, CO₂NHR⁵, CO₂R⁵, C(O)R⁵, C(O)NH₂,        C(O)NHR⁵, or C₁-C₆ alkyl optionally substituted with alkoxy,        alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic        acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,        sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   R² is H, OH, CN, NO₂, NH₂, unsubstituted C₁-C₆ alkyl,        cycloalkyl, aryl, or heteroaryl; or C₁-C₆ alkyl, cycloalkyl,        aryl, or heteroaryl substituted with alkoxy, alkenyl, alkynyl,        aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,        ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,        sulfonyl, sulfone, sulfoxide, or thiol;    -   or R¹ and R² together form a fused cycloalkyl, cycloheteroalkyl,        aryl or heteraryl group;    -   each R³ is selected, independently, from the group consisting of        SO₂NH₂, SO₂NHR⁵, NHSO₂R⁵, NHCO₂R⁵, NHC(O)R⁵, NHCONHR⁵, F, Cl,        Br, I, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloheteroaryl, and        fused cycloheteroalkyl, optionally substituted with sulfonyl;    -   each R⁵ is selected, independently, from C₁-C₆ alkyl, C₁-C₆        cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl,        any of which are optionally substituted with C₁-C₆ alkyl, C₁-C₆        alkoxyl, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino,        carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro,        silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   R⁶ is H, C₁-C₆ alkyl, CO₂R⁵, CO₂H, CO₂NHR⁵;    -   R⁷ is H, C₁-C₆ alkyl, C₁-C₆ alkoxyl, halide, hydroxyl, cyano,        nitro, or amino;    -   R⁸ is OH or ═O;    -   n is 1-5; and    -   p is 1 or 2    -   or a pharmaceutically acceptable salt thereof.

In other examples, disclosed herein are compounds of Formula IIB.

-   -   wherein    -   X is N or CH;    -   R¹ is selected from the group consisting of H, Cl, F, Br, I, CN,        NO₂, NH₂, CF₃, CO₂H, CO₂NH₂, CO₂NHR⁵, CO₂R⁵, C(O)R⁵, C(O)NH₂,        C(O)NHR⁵, or C₁-C₆ alkyl optionally substituted with alkoxy,        alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic        acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,        sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   R² is H, OH, CN, NO₂, NH₂, unsubstituted C₁-C₆ alkyl,        cycloalkyl, aryl, or heteroaryl; or C₁-C₆ alkyl, cycloalkyl,        aryl, or heteroaryl substituted with alkoxy, alkenyl, alkynyl,        aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,        ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,        sulfonyl, sulfone, sulfoxide, or thiol;    -   or R¹ and R² together form a fused cycloalkyl, cycloheteroalkyl,        aryl or heteraryl group;    -   each R³ is selected, independently, from the group consisting of        SO₂NH₂, SO₂NHR⁵, NHSO₂R⁵, NHCO₂R⁵, NHC(O)R⁵, NHCONHR⁵, F, Cl,        Br, I, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloheteroaryl, and        fused cycloheteroalkyl, optionally substituted with sulfonyl;    -   each R⁵ is selected, independently, from C₁-C₆ alkyl, C₁-C₆        cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or heteroalkyl,        any of which are optionally substituted with alkoxy, alkenyl,        alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid,        ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,        sulfonyl, sulfone, sulfoxide, or thiol;    -   R⁶ is H, C₁-C₆ alkyl, CO₂R⁵, CO₂H, CO₂NHR⁵;    -   R⁷ is H, C₁-C₆ alkyl, C₁-C₆ alkoxyl, halide, hydroxyl, cyano,        nitro, or amino;    -   R⁸ is OH or ═O;    -   n is 1-5; and    -   p is 1 or 2    -   or a pharmaceutically acceptable salt thereof.

In other examples, disclosed herein are compounds of Formula III.

-   -   wherein    -   X is N or CH;    -   L is O, S, C₁₋₄alkyl, C(O)NH, NHC(O), CH₂C(O), C(O)CH₂,        CH₂CH₂C(O), CH₂C(O)CH₂, CH₂C(O)NH, NH(CO)CH₂;    -   R¹ is selected from the group consisting of H, Cl, F, Br, I, CN,        NO₂, NH₂, CF₃, CO₂H, CO₂NH₂, CO₂NHR⁵, CO₂R⁵, C(O)R⁵, C(O)NH₂,        C(O)NHR⁵, or C₁-C₆ alkyl optionally substituted with alkoxy,        alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic        acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,        sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   R² is H, OH, CN, NO₂, NH₂, unsubstituted C₁-C₆ alkyl,        cycloalkyl, aryl, or heteroaryl; or C₁-C₆ alkyl, cycloalkyl,        aryl, or heteroaryl substituted with alkoxy, alkenyl, alkynyl,        aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,        ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,        sulfonyl, sulfone, sulfoxide, or thiol;    -   or R¹ and R² together form a fused cycloalkyl, cycloheteroalkyl,        aryl or heteraryl group;    -   each R³ is selected, independently, from the group consisting of        SO₂NH₂, SO₂NHR⁵, NHSO₂R⁵, NHCO₂R⁵, NHC(O)R⁵, NHCONHR⁵, F, Cl,        Br, I, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloheteroaryl, and        fused cycloheteroalkyl, optionally substituted with sulfonyl;    -   each R⁵ is selected, independently, from C₁-C₆ alkyl, C₁-C₆        cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or heteroalkyl,        any of which are optionally substituted with C₁-C₆ alkyl, C₁-C₆        alkoxyl, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino,        carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro,        silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   R⁶ is H, C₁-C₆ alkyl, CO₂R⁵, CO₂H, CO₂NHR⁵;    -   R⁷ is H, C₁-C₆ alkyl, C₁-C₆ alkoxyl, halide, hydroxyl, cyano,        nitro, or amino;    -   R⁸ is OH or ═O;    -   n is 1-5; and    -   p is 1 or 2    -   or a pharmaceutically acceptable salt thereof.

In certain specific examples, R¹ and R² together form a fusedcycloalkyl, cycloheteroalkyl, aryl or heteraryl group. In otherexamples, R¹ and R² together form a fused furan. In other examples, R¹and R² together form a fused cyclopentyl or fused cyclohexyl. In otherexamples, R¹ and R² together form a fused phenyl.

In certain specific examples, R¹ is C₁₋₈alkyl or heteroalkyl. In otherexamples, R¹ is methyl, ethyl, of trifluoromethyl. In other examples, R¹is chloro, bromo, or fluoro. In other examples, R¹ is CO₂C₁₋₈alkyl,CO₂H, CO₂NH₂, or CO₂NHC₁₋₈alkyl.

In certain specific examples, R² is C₁₋₈alkyl or heteroalkyl. In otherexamples, R² is hydrogen.

In the disclosed compounds there can be from 1 to 5 differentsubstituents R³, i.e., n can be 1 to 5, though preferable n can be 1 to3. In specific examples, R³ is SO₂NH₂, SO₂NHR⁵, or NHSO₂R⁵, wherein R⁵is C₁-C₆ alkyl or C₁-C₆ cycloalkyl optionally substituted with C₁-C₆alkyl, C₁-C₆ alkoxyl, hydroxyl, or halide. In other examples, R³ isNHC(O) R⁵, wherein R⁵ is C₁-C₆ alkyl or C₁-C₆ cycloalkyl optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxyl, hydroxyl, or halide. Inother examples, R³ is C₁-C₆ alkyl or C₁-C₆ cycloalkyl. In otherexamples, R³ is C₁-C₆ alkoxyl. In other examples, R³ is halide. In otherexamples, n is 2 and each R³ is selected from C₁-C₆ alkyl, C₁-C₆alkoxyl, halide, SO₂NH₂, SO₂NHR⁵, and NHSO₂R⁵, wherein R⁵ is C₁-C₆ alkylor C₁-C₆ cycloalkyl optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxyl, hydroxyl, or halide. In other examples, n is 2 and each R³ isselected from C₁-C₆ alkyl, C₁-C₆ alkoxyl, and halide. In other examples,n is 3 and each R³ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxyl, andhalide. In other examples, n is 2 and each R³ together form a fusedheterocycloalkyl.

In certain specific examples, R⁴ is C(O)NHR⁵.

In certain specific examples, R⁶ is C₁₋₈alkyl. In other examples, R⁶ ismethyl. In other examples, R⁶ is hydrogen.

In certain specific examples, R⁷ is chloro, bromo, or fluoro. In otherexamples, R⁷ is hydrogen.

In preferred examples, X is N.

In specific examples, L is CH₂(O) or C(O)NH.

In specific examples, n and m are both 1.

In specific examples R⁸ is oxo and p is 1. In other examples R⁸ is oxoand p is 2. Pharmaceutically acceptable salts of these compounds arealso disclosed.

Specific examples of compounds having Formula I, IIA, IIB, and III aredisclosed herein are in Table 1.

TABLE 1 Estimated Co- DSF ΔTm BRD4 Name crystal (° C.) IC₅₀ (μM)Comments

No N/A

Yes (1.3 Å) 4.8 ± 0.058 0.54 HEK293 (IC₅₀ = 1.4 μM) MM.1S (IC₅₀ = 0.45μM)

Yes (1.3 Å) 5.6 ± 0.082 0.29 (IC₅₀ RB = 0.617) HEK293 (IC₅₀ = 0.38 μM)MM.1S (IC₅₀ = 0.42 μM) BRD2 IC₅₀ = 2.80 × 10³ nM BRD3 IC₅₀ = 1.14 × 10³nM BRD4 IC₅₀ = 617 nM BRDT IC₅₀ = 1.40 × 10³ nM JAK1 IC₅₀ = 1.83 nM JAK2IC₅₀ = 0.690 nM JAK3 IC₅₀ = 9.06 nM

No  0.12 ± 0.053 19.78

No 0.56 ± 0.37 14.10

Partial (1.65 Å)  4.6 ± 0.12 0.63

No −.071 ± 0.042 22.91

Yes (2.6 Å)  5.7 ± 0.054 0.27

No  2.9 ± 0.12 2.33

No 0.16 19.18

No 2.2 3.99

No −0.79 39.83

No −0.29 27.11

No −0.34 28.18

No N/A

No N/A

Yes 5.0 0.46

No −0.0084 21.83

No N/A

No N/A

No 3.2 1.85

No N/A Dinaciclib Yes 0.53 17.22 BRD4 IC₅₀ = 19 μM (RB)

Yes  6.83 ± 0.129  7.55 ± 0.154 0.13 0.186 MM.1S IC₅₀ = 1.58 nM MV-4-11IC₅₀ = 122 nM SAOS-2 IC₅₀ = 425 nM UKE-1 IC₅₀ = 689 nM BRD4 IC₅₀ = 0.13μM (RB) BRD2 IC₅₀ = 2.35 × 10³ nM BRD3 IC₅₀ = 477 nM BRD4 IC₅₀ = 518 nMBRDT IC₅₀ = 840 nM (RB) JAK1 IC₅₀ = 2.63 nM JAK2 IC₅₀ = 0.508 nM JAK3IC₅₀ = 97.6 nM FLT3 IC₅₀ = 1.53 nM (RB)

No  5.3 ± 0.064 0.37 HEK293 (IC₅₀ = 120 μM)

No  1.9 ± 0.17 5.03

No 0.22 ± 0.20 18.31

No 0.12 ± 0.13 19.78

No N/A

Yes (1.97 Å)  6.7 ± 0.11 0.13 HEK293 (IC₅₀ = 1.0 μM) MM.1S (IC₅₀ = 0.60μM)

No  4.1 ± 0.14 0.93 JAK2 (IC₅₀ RB = 14 μM) HEK293 (IC₅₀ = 0.84 μM)

Yes (1.35 Å)  5.9 ± 0.14 0.23 HEK293 (IC₅₀ = 1.4 μM) MM.1S (IC₅₀ = 5.6μM)

Partial (1.52 Å)  6.0 ± 0.10 0.21

No  0.20 ± 0.082 18.60

No  2.9 ± 0.031 2.33

No  5.2 ± 0.020 0.40 HEK293 (IC₅₀ = 2.0 μM)

No  2.6 ± 0.15 2.94

No 0.073 ± 0.083 20.51

No 0.073 ± 0.13  20.51

No  1.3 ± 0.11 7.98

No  1.68 ± 0.078 5.96

Yes (1.75 Å)  4.3 ± 0.12 0.79

Yes (1.75 Å)  5.6 ± 0.059 0.29

No  5.1 ± 0.039 0.43

Yes (1.75 Å)  3.2 ± 0.083 1.85

Yes (1.88 Å)  5.4 ± 0.15 0.34

No . N/A

Yes (1.70 Å)  7.3 ± 0.099 0.079 HEK293 (IC₅₀ = 1.2 μM) MM.1S (IC₅₀ = 1.2μM)

Yes (1.84 Å)  6.9 ± 0.15 0.11 HEK293 (IC₅₀ = 3.6 μM)

Yes (1.93 Å)  6.4 ± 0.15 0.16 HEK293 (IC₅₀ = 1.8 μM) MM.1S (IC₅₀ = 0.88μM)

Yes (1.70 Å)  4.8 ± 0.12 0.54

Yes (1.78 Å)  6.6 ± 0.10 0.14

No 0.24 ± 0.13 18

No −0.0056 ± 0.24   >20

 6.9 ± 0.10 0.11 HEK293 (IC₅₀ = 0.97 μM)

Partial (1.70 Å)  4.4 ± 0.11 0.74

No  0.79 ± 0.079 12

  2 ± 0.42 4.7

Yes (1.54 Å)  7.6 ± 0.15 0.063 MM.1S (IC₅₀ = 1.1 μM)

 2.6 ± 0.095 2.9

0.57 ± 0.25 14

Yes (1.50 Å)  7.1 ± 0.15 0.092

 6.1 ± 0.15 0.2 HEK293 (IC₅₀ = 1.5 μM)

 6.5 ± 0.18 0.15 HEK293 (IC₅₀ = 3.6 μM)

 5.5 ± 0.17 0.32 HEK293 (IC₅₀ = 4.3 μM)

 3.5 ± 0.17 1.5

No  2.5 ± 0.069 3.2

Yes (1.42 Å) n/a

Yes (1.60 Å)  3.1 ± 0.075 2.0

No  1.4 ± 0.11 7.4

Yes (1.60 Å)  4.5 ± 0.10 0.68

Yes (1.76 Å)  8.54 ± 0.088 0.025 JAK2 (IC₅₀ RB = 0.4 nM) HEK293 (IC₅₀ =1.2 μM) MM.1S (IC₅₀ = 0.40 μM) Saos-2 IC₅₀ = = 184 nM UKE-1 IC₅₀ = 260nM BRD2 IC₅₀ = 625 nM BRD3 IC₅₀ = 12.5 nM BRD4 IC₅₀ = 10.2 nM BRDT IC₅₀= 29.1 nM (RB) JAK1 IC₅₀ = 4.58 nM JAK2 IC₅₀ = 2.70 nM JAK3 IC₅₀ = 91.4nM FLT3 IC₅₀ = 0.917 nM (RB)

Yes (1.42 Å) 3.7 ± 0.12 1.3

Yes (1.55 Å)   6.4 ± 0.0066 0.16

Partial (1.57 Å)  4.9 ± 0.13 0.5 HEK293 (IC₅₀ = 1.7 μM)

Yes  6.3 ± 0.10 0.17

 2.6 ± 0.081 2.9

 4.6 ± 0.13 0.63

 5.8 ± 0.11 0.26

 3.5 ± 0.19 1.5

 4.1 ± 0.12 0.90

 4.6 ± 0.21 0.63

 2.1 ± 0.10 4.3

 5.0 ± 0.13 0.48

−0.20 ± 0.20  25

0.0094 ± 0.11  22

 6.1 ± 0.032 0.20

Yes  8.6 ± 0.090 0.030

N/A

  2.7 ± 0.0089 2.7

 4.9 ± 0.11 0.50

 3.8 ± 0.056 1.2

 4.9 ± 0.099 0.52

0.60 ± 0.14 14

 2.9 ± 0.084 2.3

 3.9 ± 0.24 1.0

 1.3 ± 0.12 7.9

 6.0 ± 0.13 0.22

 6.4 ± 0.12 0.15

 4.3 ± 0.14 0.77

 2.3 ± 0.073 3.8

Yes  7.0 ± 0.14 0.10

N/A

  4.6 ± 0.050Δ 0.62

 5.4 ± 0.20 0.35

Yes  9.57 ± 0.086 0.010 MM.1S IC₅₀ = 0.074 μM MM1.S (IC₅₀ = 0.142 μM)MV-4-11 IC₅₀ = 186 nM SAOS-2 IC₅₀ = 567 nM UKE-1 IC₅₀ = 512 nM BRD2 IC₅₀= 81.4 nM BRD3 IC₅₀ = 16.5 nM BRD4 IC₅₀ = 4.04 nM BRDT IC₅₀ = 27.8 nM(RB) JAK2 IC₅₀ = 11.2 nM FLT3 IC₅₀ = 9.71 nM Solubility 650 uM in PBSbuffer (~9.3% DMSO) = 0.416 mg SG3-014B2.MSA in 1 mL PBS buffer (~9.3%DMSO) Solubility > 14.4 mg SG3-014B2.MSA in 1 mL PBS buffer (15% HPCD)

 5.2 ± 0.15 0.40

 6.9 ± 0.038 0.11 MM1.S (IC₅₀ = 1.7 μM) Saos-2 (IC₅₀ = 2.5 μM)

 7.2 ± 0.17 0.085

 3.0 ± 0.11 2.2

NA NA

 5.9 ± 0.063 2.3

 7.6 ± 0.047 0.062

 3.3 ± 0.36 1.8

 0.35 ± 0.068 17

 3.4 ± 0.27 1.6

 7.6 ± 0.28 0.061

n/a

 6.5 ± 0.11 0.15

 6.8 ± 0.15 0.11

 4.2 ± 0.20 0.85

yes   10 ± 0.11   10 ± 0.11 0.0074 0.0099 UKE-1 (IC₅₀ = 0.47 μM) MV-4-11(IC₅₀ = 0.098 μM)

Yes   11 ± 0.12   11 ± 0.12 0.0061 0.0046 UKE-1 (IC₅₀ = 1.6 μM) MV-4-11(IC₅₀ = 0.071 μM)

 9.2 ± 0.12 0.018

 4.1 ± 0.07 0.900

 4.1 ± 0.10 0.960

Yes  9.5 ± 0.14 11.2 ± 0.15 0.014 0.0039 MM1.S (IC₅₀ = 0.16 μM) (IC₅₀ =0.146 μM) Saos-2 IC₅₀ = 0.133 μM) NCI-H2052 (IC₅₀ = 1.4 μM) UKE-1 (IC₅₀= 0.200 μM) MV-4-11 (IC₅₀ = 0.0268 μM) JAK2 IC₅₀ = 1.14 nM FLT3 IC₅₀ =1.10 nM BRD4-1 (BRD4-2) (IC₅₀ = 24.3 (22.0) nM) BRDT-1 (IC₅₀ = 41.3 nM)

Yes   11 ± 0.04  12.6 ± 0.069 0.0048 0.0013 MM1.S (IC₅₀ = 0.059 μM)(IC₅₀ = 0.064 μM) (IC₅₀ = 0.066 μM) Saos-2 (IC₅₀ = 0.320 μM) NCI-H2052(IC₅₀ = 2.5 μM) UKE-1 (IC₅₀ = 0.294 μM) MV-4-11 (IC₅₀ = 0.0532 μM) JAK2IC₅₀ = 0.3.36 nM FLT3 IC₅₀ = 10.7 nM BRD4-1 (BRD-2) (IC₅₀ = 11.2 (17.5)nM BRDT-1 (IC₅₀ = 19.0 nM)

 7.5 ± 0.14 0.066

 9.5 ± 0.07 0.014

 5.3 ± 0.041 0.370

 2.0 ± 0.05 4.70

 8.4 ± 0.13 0.034

 4.1 ± 0.21 0.930

 4.7 ± 0.14 0.580

 6.7 ± 0.15 0.130

Yes  12.5 ± 0.165 0.0013 MM1.S (IC₅₀ = 0.057 μM, n = 2) NCI-II2052 (IC₅₀= >10 μM) UKE-1 (IC₅₀ = 0.22 μM) MV-4-11 (IC₅₀ = 0.038 μM) JAK2 (IC₅₀ =0.012 μM) FLT3 (IC₅₀ = 0.032 μM) BRD4-1 (IC₅₀ = 0.010 μM) BRDT-1 (IC₅₀ =0.023 μM)

 9.8 ± 0.03 0.012

 3.4 ± 0.12 1.60

 6.7 ± 0.13 0.130

 7.8 ± 0.15 0.054

 6.8 ± 0.01 0.120

 3.1 ± 0.08 2.00

 7.7 ± 0.17 0.058

 7.5 ± 0.23 0.068

 9.1 ± 0.05 0.020

 6.70 ± 0.157 0.321

 6.58 ± 0.103 0.347

 9.91 ± 0.039 0.0405 MM1.S (IC₅₀ = 0.12 μM)

0.570 ± 0.124 Precipitation observed in DSF buffer 16.8 MM1.S (IC₅₀ =0.16 μM)

12.0 ± 0.50 0.0105 MM1.S (IC₅₀ = 0.090 μM)

 5.22 ± 0.065 Precipitation observed in DSF buffer 0.835 MM1.S (IC₅₀ =0.11 μM)

 7.93 ± 0.183 0.145

 7.28 ± 0.091 0.221

 8.89 ± 0.044 0.0748

 9.97 ± 0.080 0.039

 12.1 ± 0.105 0.0098

 12.3 ± 0.116 0.0086

 8.72 ± 0.141 0.0873

 10.5 ± 0.150 0.0277

 11.4 ± 0.103 0.0155

 9.54 ± 0.163 0.0514

 10.4 ± 0.151 0.0295

 12.8 ± 0.058 0.00628

 8.12 ± 0.044 0.129

 13.8 ± 0.191 0.00329

 2.46 ± 0.111 Precipitation interferes with the assay 4.95

 12.3 ± 0.167 0.0086

10.9 ± 0.22 0.021

 3.17 ± 0.142 3.13

In other examples, disclosed herein are compounds of Formula IV:

where R¹, R², R⁴ and R⁷ are as defined herein. For example, in FormulaIV:

-   -   R¹ is selected from the group consisting of H, Cl, F, Br, I, CN,        NO₂, NH₂, CF₃, CO₂H, CO₂NH₂, CO₂NHR⁵, CO₂R⁵, C(O)R⁵, C(O)NH₂,        C(O)NHR⁵, or C₁-C₆ alkyl optionally substituted with alkoxy,        alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic        acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,        sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;    -   R² is H, OH, CN, NO₂, NH₂, unsubstituted C₁-C₆ alkyl,        cycloalkyl, aryl, or heteroaryl; or C₁-C₆ alkyl, cycloalkyl,        aryl, or heteroaryl substituted with alkoxy, alkenyl, alkynyl,        aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,        ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,        sulfonyl, sulfone, sulfoxide, or thiol;    -   or R¹ and R² together form a fused cycloalkyl, cycloheteroalkyl,        aryl or heteraryl group;    -   each R⁴ is selected, independently, from the group consisting of        F, Cl, Br, I, NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, COOH, C(O)NH₂,        C(O)R⁵, C(O)NHR⁵, CH₂C(O)R⁵, SO₂NH₂, SO₂NHR⁵, or CONHSO₂R⁵, or        phenyl, OPhenyl, tetrazole, piperadinyl, piperazinyl,        morpholinyl, optionally substituted with alkoxy, alkenyl,        alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid,        ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo,        sulfonyl, sulfone, sulfoxide, or thiol;    -   each R⁵ is selected, independently, from C₁-C₆ alkyl, C₁-C₆        cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or heteroalkyl,        any of which are optionally substituted with C₁-C₆ alkyl, C₁-C₆        alkoxyl, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino,        carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro,        silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol;        -   R⁷ is H, C₁-C₆ alkyl, C₁-C₆ alkoxyl, halide, hydroxyl,            cyano, nitro, or amino; and    -   m is 1-5 or a pharmaceutically acceptable salt thereof.

Specific Examples of compounds having Formula IV are shown in Table 2.

TABLE 2 Compound Code (Structure) MW Co-crystal

401.7 No

415.7 No

419.7 No

428.7 No

471.9 No

457.9 No

426.3 No

686.9 No

402.9 No

401.9 No

431.9 No

496.4 No

431.9 No

358.8 No

354.8 No

415.7 No

426.3 No

402.9 No

DSF=Differential Scanning Fluorimetry; provides a measure of theincreased stability of BRD4 upon ligand binding The DSF experiment wasrun at 100 μM protein, 4 μM compound and 2% DMSO.

Method

Further provided herein are methods of treating or preventing cancer ina subject, comprising administering to the subject an effective amountof a compound or composition as disclosed herein. The methods canfurther comprise administering a second compound or composition, suchas, for example, anticancer agents or anti-inflammatory agents.Additionally, the method can further comprise administering an effectiveamount of ionizing radiation to the subject.

Methods of killing a tumor cell are also provided herein. The methodscomprise contacting a tumor cell with an effective amount of a compoundor composition as disclosed herein. The methods can further includeadministering a second compound or composition (e.g., an anticanceragent or an anti-inflammatory agent) or administering an effectiveamount of ionizing radiation to the subject.

Also provided herein are methods of radiotherapy of tumors, comprisingcontacting the tumor with an effective amount of a compound orcomposition as disclosed herein and irradiating the tumor with aneffective amount of ionizing radiation.

Also disclosed are methods for treating oncological disorders in apatient. In one embodiment, an effective amount of one or more compoundsor compositions disclosed herein is administered to a patient having anoncological disorder and who is in need of treatment thereof.

The disclosed methods can optionally include identifying a patient whois or can be in need of treatment of an oncological disorder. Thepatient can be a human or other mammal, such as a primate (monkey,chimpanzee, ape, etc.), dog, cat, cow, pig, or horse, or other animalshaving an oncological disorder. Oncological disorders include, but arenot limited to, cancer and/or tumors of the anus, bile duct, bladder,bone, bone marrow, bowel (including colon and rectum), breast, eye, gallbladder, kidney, mouth, larynx, esophagus, stomach, testis, cervix,head, neck, ovary, lung, mesothelioma, neuroendocrine, penis, skin,spinal cord, thyroid, vagina, vulva, uterus, liver, muscle, pancreas,prostate, blood cells (including lymphocytes and other immune systemcells), and brain. Specific cancers contemplated for treatment includecarcinomas, Karposi's sarcoma, melanoma, mesothelioma, soft tissuesarcoma, pancreatic cancer, lung cancer, leukemia (acute lymphoblastic,acute myeloid, chronic lymphocytic, chronic myeloid, and other), andlymphoma (Hodgkin's and non-Hodgkin's), and multiple myeloma.

Administration

The disclosed compounds can be administered either sequentially orsimultaneously in separate or combined pharmaceutical formulations. Whenone or more of the disclosed compounds is used in combination with asecond therapeutic agent the dose of each compound can be either thesame as or differ from that when the compound is used alone. Appropriatedoses will be readily appreciated by those skilled in the art.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

In vivo application of the disclosed compounds, and compositionscontaining them, can be accomplished by any suitable method andtechnique presently or prospectively known to those skilled in the art.For example, the disclosed compounds can be formulated in aphysiologically- or pharmaceutically-acceptable form and administered byany suitable route known in the art including, for example, oral, nasal,rectal, topical, and parenteral routes of administration. As usedherein, the term parenteral includes subcutaneous, intradermal,intravenous, intramuscular, intraperitoneal, and intrasternaladministration, such as by injection. Administration of the disclosedcompounds or compositions can be a single administration, or atcontinuous or distinct intervals as can be readily determined by aperson skilled in the art.

The compounds disclosed herein, and compositions comprising them, canalso be administered utilizing liposome technology, slow releasecapsules, implantable pumps, and biodegradable containers. Thesedelivery methods can, advantageously, provide a uniform dosage over anextended period of time. The compounds can also be administered in theirsalt derivative forms or crystalline forms.

The compounds disclosed herein can be formulated according to knownmethods for preparing pharmaceutically acceptable compositions.Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by E.W. Martin (1995)describes formulations that can be used in connection with the disclosedmethods. In general, the compounds disclosed herein can be formulatedsuch that an effective amount of the compound is combined with asuitable carrier in order to facilitate effective administration of thecompound. The compositions used can also be in a variety of forms. Theseinclude, for example, solid, semi-solid, and liquid dosage forms, suchas tablets, pills, powders, liquid solutions or suspension,suppositories, injectable and infusible solutions, and sprays. Thepreferred form depends on the intended mode of administration andtherapeutic application. The compositions also preferably includeconventional pharmaceutically-acceptable carriers and diluents which areknown to those skilled in the art. Examples of carriers or diluents foruse with the compounds include ethanol, dimethyl sulfoxide, glycerol,alumina, starch, saline, and equivalent carriers and diluents. Toprovide for the administration of such dosages for the desiredtherapeutic treatment, compositions disclosed herein can advantageouslycomprise between about 0.1% and 99%, and especially, 1 and 15% by weightof the total of one or more of the subject compounds based on the weightof the total composition including carrier or diluent.

Formulations suitable for administration include, for example, aqueoussterile injection solutions, which can contain antioxidants, buffers,bacteriostats, and solutes that render the formulation isotonic with theblood of the intended recipient; and aqueous and nonaqueous sterilesuspensions, which can include suspending agents and thickening agents.The formulations can be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in a freezedried (lyophilized) condition requiring only the condition of thesterile liquid carrier, for example, water for injections, prior to use.Extemporaneous injection solutions and suspensions can be prepared fromsterile powder, granules, tablets, etc. It should be understood that inaddition to the ingredients particularly mentioned above, thecompositions disclosed herein can include other agents conventional inthe art having regard to the type of formulation in question.

Compounds disclosed herein, and compositions comprising them, can bedelivered to a cell either through direct contact with the cell or via acarrier means. Carrier means for delivering compounds and compositionsto cells are known in the art and include, for example, encapsulatingthe composition in a liposome moiety. Another means for delivery ofcompounds and compositions disclosed herein to a cell comprisesattaching the compounds to a protein or nucleic acid that is targetedfor delivery to the target cell. U.S. Pat. No. 6,960,648 and U.S.Application Publication Nos. 20030032594 and 20020120100 disclose aminoacid sequences that can be coupled to another composition and thatallows the composition to be translocated across biological membranes.U.S. Application Publication No. 20020035243 also describes compositionsfor transporting biological moieties across cell membranes forintracellular delivery. Compounds can also be incorporated intopolymers, examples of which include poly (D-L lactide-co-glycolide)polymer for intracranial tumors; poly[bis(p-carboxyphenoxy)propane:sebacic acid] in a 20:80 molar ratio (as used in GLIADEL);chondroitin; chitin; and chitosan.

For the treatment of oncological disorders, the compounds disclosedherein can be administered to a patient in need of treatment incombination with other antitumor or anticancer substances and/or withradiation and/or photodynamic therapy and/or with surgical treatment toremove a tumor. These other substances or treatments can be given at thesame as or at different times from the compounds disclosed herein. Forexample, the compounds disclosed herein can be used in combination withmitotic inhibitors such as taxol or vinblastine, alkylating agents suchas cyclophosamide or ifosfamide, antimetabolites such as 5-fluorouracilor hydroxyurea, DNA intercalators such as adriamycin or bleomycin,topoisomerase inhibitors such as etoposide or camptothecin,antiangiogenic agents such as angiostatin, antiestrogens such astamoxifen, and/or other anti-cancer drugs or antibodies, such as, forexample, GLEEVEC (Novartis Pharmaceuticals Corporation) and HERCEPTIN(Genentech, Inc.), respectively.

Many tumors and cancers have viral genome present in the tumor or cancercells. For example, Epstein-Barr Virus (EBV) is associated with a numberof mammalian malignancies. The compounds disclosed herein can also beused alone or in combination with anticancer or antiviral agents, suchas ganciclovir, azidothymidine (AZT), lamivudine (3TC), etc., to treatpatients infected with a virus that can cause cellular transformationand/or to treat patients having a tumor or cancer that is associatedwith the presence of viral genome in the cells. The compounds disclosedherein can also be used in combination with viral based treatments ofoncologic disease. For example, the compounds can be used with mutantherpes simplex virus in the treatment of non-small cell lung cancer(Toyoizumi, et al., “Combined therapy with chemotherapeutic agents andherpes simplex virus type IICP34.5 mutant (HSV-1716) in human non-smallcell lung cancer,” Human Gene Therapy, 1999, 10(18):17).

Therapeutic application of compounds and/or compositions containing themcan be accomplished by any suitable therapeutic method and techniquepresently or prospectively known to those skilled in the art. Further,compounds and compositions disclosed herein have use as startingmaterials or intermediates for the preparation of other useful compoundsand compositions.

Compounds and compositions disclosed herein can be locally administeredat one or more anatomical sites, such as sites of unwanted cell growth(such as a tumor site or benign skin growth, e.g., injected or topicallyapplied to the tumor or skin growth), optionally in combination with apharmaceutically acceptable carrier such as an inert diluent. Compoundsand compositions disclosed herein can be systemically administered, suchas intravenously or orally, optionally in combination with apharmaceutically acceptable carrier such as an inert diluent, or anassimilable edible carrier for oral delivery. They can be enclosed inhard or soft shell gelatin capsules, can be compressed into tablets, orcan be incorporated directly with the food of the patient's diet. Fororal therapeutic administration, the active compound can be combinedwith one or more excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,aerosol sprays, and the like.

The tablets, troches, pills, capsules, and the like can also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring can be added. Whenthe unit dosage form is a capsule, it can contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials can be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules can be coatedwith gelatin, wax, shellac, or sugar and the like. A syrup or elixir cancontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound canbe incorporated into sustained-release preparations and devices.

Compounds and compositions disclosed herein, including pharmaceuticallyacceptable salts, hydrates, or analogs thereof, can be administeredintravenously, intramuscularly, or intraperitoneally by infusion orinjection. Solutions of the active agent or its salts can be prepared inwater, optionally mixed with a nontoxic surfactant. Dispersions can alsobe prepared in glycerol, liquid polyethylene glycols, triacetin, andmixtures thereof and in oils. Under ordinary conditions of storage anduse, these preparations can contain a preservative to prevent the growthof microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient, which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. The ultimatedosage form should be sterile, fluid and stable under the conditions ofmanufacture and storage. The liquid carrier or vehicle can be a solventor liquid dispersion medium comprising, for example, water, ethanol, apolyol (for example, glycerol, propylene glycol, liquid polyethyleneglycols, and the like), vegetable oils, nontoxic glyceryl esters, andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the formation of liposomes, by the maintenance of therequired particle size in the case of dispersions or by the use ofsurfactants. Optionally, the prevention of the action of microorganismscan be brought about by various other antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the inclusion of agents that delay absorption, forexample, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating a compoundand/or agent disclosed herein in the required amount in the appropriatesolvent with various other ingredients enumerated above, as required,followed by filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, compounds and agents disclosed herein can beapplied in as a liquid or solid. However, it will generally be desirableto administer them topically to the skin as compositions, in combinationwith a dermatologically acceptable carrier, which can be a solid or aliquid. Compounds and agents and compositions disclosed herein can beapplied topically to a subject's skin to reduce the size (and caninclude complete removal) of malignant or benign growths, or to treat aninfection site. Compounds and agents disclosed herein can be applieddirectly to the growth or infection site. Preferably, the compounds andagents are applied to the growth or infection site in a formulation suchas an ointment, cream, lotion, solution, tincture, or the like. Drugdelivery systems for delivery of pharmacological substances to dermallesions can also be used, such as that described in U.S. Pat. No.5,167,649.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers, for example.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user. Examples of useful dermatological compositionswhich can be used to deliver a compound to the skin are disclosed inU.S. Pat. No. 4,608,392; U.S. Pat. No. 4,992,478; U.S. Pat. No.4,559,157; and U.S. Pat. No. 4,820,508.

Useful dosages of the compounds and agents and pharmaceuticalcompositions disclosed herein can be determined by comparing their invitro activity, and in vivo activity in animal models. Methods for theextrapolation of effective dosages in mice, and other animals, to humansare known to the art; for example, see U.S. Pat. No. 4,938,949.

Also disclosed are pharmaceutical compositions that comprise a compounddisclosed herein in combination with a pharmaceutically acceptablecarrier. Pharmaceutical compositions adapted for oral, topical orparenteral administration, comprising an amount of a compound constitutea preferred aspect. The dose administered to a patient, particularly ahuman, should be sufficient to achieve a therapeutic response in thepatient over a reasonable time frame, without lethal toxicity, andpreferably causing no more than an acceptable level of side effects ormorbidity. One skilled in the art will recognize that dosage will dependupon a variety of factors including the condition (health) of thesubject, the body weight of the subject, kind of concurrent treatment,if any, frequency of treatment, therapeutic ratio, as well as theseverity and stage of the pathological condition.

For the treatment of oncological disorders, compounds and agents andcompositions disclosed herein can be administered to a patient in needof treatment prior to, subsequent to, or in combination with otherantitumor or anticancer agents or substances (e.g., chemotherapeuticagents, immunotherapeutic agents, radiotherapeutic agents, cytotoxicagents, etc.) and/or with radiation therapy and/or with surgicaltreatment to remove a tumor. For example, compounds and agents andcompositions disclosed herein can be used in methods of treating cancerwherein the patient is to be treated or is or has been treated withmitotic inhibitors such as taxol or vinblastine, alkylating agents suchas cyclophosamide or ifosfamide, antimetabolites such as 5-fluorouracilor hydroxyurea, DNA intercalators such as adriamycin or bleomycin,topoisomerase inhibitors such as etoposide or camptothecin,antiangiogenic agents such as angiostatin, antiestrogens such astamoxifen, and/or other anti-cancer drugs or antibodies, such as, forexample, GLEEVEC (Novartis Pharmaceuticals Corporation) and HERCEPTIN(Genentech, Inc.), respectively. These other substances or radiationtreatments can be given at the same as or at different times from thecompounds disclosed herein. Examples of other suitable chemotherapeuticagents include, but are not limited to, altretamine, bleomycin,bortezomib (VELCADE), busulphan, calcium folinate, capecitabine,carboplatin, carmustine, chlorambucil, cisplatin, cladribine,crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide,fludarabine, fluorouracil, gefitinib (IRESSA), gemcitabine, hydroxyurea,idarubicin, ifosfamide, imatinib (GLEEVEC), irinotecan, liposomaldoxorubicin, lomustine, melphalan, mercaptopurine, methotrexate,mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pentostatin,procarbazine, raltitrexed, streptozocin, tegafur-uracil, temozolomide,thiotepa, tioguanine/thioguanine, topotecan, treosulfan, vinblastine,vincristine, vindesine, vinorelbine. In an exemplified embodiment, thechemotherapeutic agent is melphalan. Examples of suitableimmunotherapeutic agents include, but are not limited to, alemtuzumab,cetuximab (ERBITUX), gemtuzumab, iodine 131 tositumomab, rituximab,trastuzamab (HERCEPTIN). Cytotoxic agents include, for example,radioactive isotopes (e.g., I¹³¹, I¹²⁵, Y⁹⁰, P³², etc.), and toxins ofbacterial, fungal, plant, or animal origin (e.g., ricin, botulinumtoxin, anthrax toxin, aflatoxin, jellyfish venoms (e.g., box jellyfish),etc.) Also disclosed are methods for treating an oncological disordercomprising administering an effective amount of a compound and/or agentdisclosed herein prior to, subsequent to, and/or in combination withadministration of a chemotherapeutic agent, an immunotherapeutic agent,a radiotherapeutic agent, or radiotherapy.

Kits

Kits for practicing the methods of the invention are further provided.By “kit” is intended any manufacture (e.g., a package or a container)comprising at least one reagent, e.g., anyone of the compounds describedin Table 1. The kit may be promoted, distributed, or sold as a unit forperforming the methods of the present invention. Additionally, the kitsmay contain a package insert describing the kit and methods for its use.Any or all of the kit reagents may be provided within containers thatprotect them from the external environment, such as in sealed containersor pouches.

To provide for the administration of such dosages for the desiredtherapeutic treatment, in some embodiments, pharmaceutical compositionsdisclosed herein can comprise between about 0.1% and 45%, andespecially, 1 and 15%, by weight of the total of one or more of thecompounds based on the weight of the total composition including carrieror diluents. Illustratively, dosage levels of the administered activeingredients can be: intravenous, 0.01 to about 20 mg/kg;intraperitoneal, 0.01 to about 100 mg/kg; subcutaneous, 0.01 to about100 mg/kg; intramuscular, 0.01 to about 100 mg/kg; orally 0.01 to about200 mg/kg, and preferably about 1 to 100 mg/kg; intranasal instillation,0.01 to about 20 mg/kg; and aerosol, 0.01 to about 20 mg/kg of animal(body) weight.

Also disclosed are kits that comprise a composition comprising acompound disclosed herein in one or more containers. The disclosed kitscan optionally include pharmaceutically acceptable carriers and/ordiluents. In one embodiment, a kit includes one or more othercomponents, adjuncts, or adjuvants as described herein. In anotherembodiment, a kit includes one or more anti-cancer agents, such as thoseagents described herein. In one embodiment, a kit includes instructionsor packaging materials that describe how to administer a compound orcomposition of the kit. Containers of the kit can be of any suitablematerial, e.g., glass, plastic, metal, etc., and of any suitable size,shape, or configuration. In one embodiment, a compound and/or agentdisclosed herein is provided in the kit as a solid, such as a tablet,pill, or powder form. In another embodiment, a compound and/or agentdisclosed herein is provided in the kit as a liquid or solution. In oneembodiment, the kit comprises an ampoule or syringe containing acompound and/or agent disclosed herein in liquid or solution form.

Method of Screening

Also disclosed herein are methods of identifying a putative anti-cancercompound comprising contacting BRD4 with a target compound anddetermining whether the compound binds the BRD4, wherein the compoundthat binds BRD4 is identified as a putative anti-cancer compound.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

First, a set of 2-chloro-4-anilinopyrimidines 2 is be prepared byreaction of the 5-substituted dichloropyrimidine 1 (R⁴=Me, Et, CF₃, Cl,F, Br, CN, CCH) with appropriate aniline bearing R¹ and R² groups.Reaction of building blocks 2 with a set of anilines bearing the R groupwill provide the target set of dianilinopyrimidines 3. This modulartwo-step synthesis will provide rapid access to libraries for analysisof both BRD4 and kinase inhibitory properties.

Cellular activity of promising compounds is assessed using MM.1S andMV4-11 AML cells using c-Myc levels as biomarker (6-12 hr treatment) andantiproliferative activity (48-72 hr treatment) as described (Ciceri etal., Dual kinase-bromodomain inhibitors for rationally designedpolypharmacology. Nat Chem Biol 2014). The most potent BRD4 inhibitorsare profiled against representative panels of kinases and BRDs to assesspotency and specificity using commercial services.

Example 1: General Synthetic Routes

The dianilinopyrimidines were prepared according to Scheme 1 usingmethods reported by (Lawrence, et al., Development of novel ACK1/TNK2inhibitors using a fragment-based approach. J Med Chem 2015, 58,2746-63; Lawrence, et al., Development of o-chlorophenyl substitutedpyrimidines as exceptionally potent aurora kinase inhibitors. J. Med.Chem. 2012, 55, 7392-416). Specifically, a substituted2,4-dichloropyrimidine 1 was reacted with with A-ring aniline 2 to formthe 4-anilino-pyrimidine intermediate 3. This intermediate 3, uponreaction with a second set of B-ring anilines 4 under more forcingconditions, generated the final dianilinopyrimidine library 5.Alternatively the reaction of the 4-anilino-pyrimidine intermediate 3and the B-ring aniline may be effected by palladium catalysis. Analternative approach to certain sulfonamide substituted B-rings involvessulfonylation of dianilinopyrimidine (Scheme 1B). When the pyrimidinehas a trifluoromethyl group at position 5, the targetdianilinopyrimidine is prepared by the route shown in Scheme 1C.Regioselective reaction (Richter, et al., Selective addition of aminesto 5-trifluoromethyl-2,4-dichloropyrimidine induced by Lewis acids.Tetrahedron Letters 2013, 54, 4610-4612) of an aniline with5-(trifluoromethyl)-2,4-dichloropyrimidine (6) provides the4-chloropyrimidine 7. Reaction with the B-ring aniline providesSG2-029-01 a precursor to SG2-033-01-1.

The intermediate 2,4-dichloropyrimidines 1 were prepared from thecorresponding pyrimidine-2,4(1H,3H)-dione 8 (prepared using reportedmethods (McIver, et al., Synthesis and structure-activity relationshipsof a novel series of pyrimidines as potent inhibitors of TBK1/IKKepsilonkinases. Bioorg Med Chem Lett 2012, 22, 7169-73) shown in Scheme 2A) bytreatment with phosphorus oxychloride (Scheme 2). The2,4-dichloro-5,6-dimethylpyrimidine was prepared according to the route(Zhang, et al., Design and synthesis of pyrimidinone and pyrimidinedioneinhibitors of dipeptidyl peptidase IV. J Med Chem 2011, 54, 510-24)shown in Schemes 2B. The preparation of 2,4-dichloropyrimidines in whichthe 5 and 6 positions are part of a further ring (MA2-092, MA2-096,MA2-028 and MA3-034) (US2005/0256125) is shown in Schemes 2C and 2D.

The A-ring anilines with an amide, urea or alkoxy group were synthesizedfrom nitroaniline and nitroisocyanate precursors via standard methods(WO2008/122667; Ueda, et al., Copper-catalyzed synthesis of benzoxazolesvia a regioselective C—H functionalization/C—O bond formation under anair atmosphere. J Org Chem 2009, 74, 4272-7; WO2011/039735) ENREF 7according to the routes shown in Schemes 3A and 3B. The anilines MA1-086and MA1-087 were prepared by O-alkylation of 2-chloro-5-aminophenol(Scheme 3C) (WO2011/119704).

The synthetic routes to the A-ring anilines bearing a sulfonamide groupare shown in Schemes 4A-D. Those shown in Scheme 4A were prepared byreaction of nitrophenylsulfonyl chlorides and amines, followed byreduction of the nitro group (Lawrence, et al., Synthesis and biologicalevaluation of naphthoquinone analogs as a novel class of proteasomeinhibitors. Bioorg Med Chem 2010, 18, 5576-92). A similar approach isshown for those B-ring anilines prepared from nitroaniline or mono-BOCdiaminobenzene derivatives as shown in Scheme 4B (Altenbach, et al.,Synthesis and structure-activity studies onN-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide,an imidazole-containing alpha(1A)-adrenoceptor agonist. J Med Chem 2004,47, 3220-35). The B-ring aniline bearing a tert-butylsulfonamide(MA3-098, MA3-010, SG3-105, SG3-124, SG4-020 and SG4-023) were preparedby tert-butylsulfinylation followed by oxidation of the intermediatetert-butylsulfinamides by standard methods as shown in Scheme 4C (Sun,et al., tert-Butylsulfonyl (Bus), a New Protecting Group for Amines. JOrg Chem 1997, 62, 8604-8608). The synthesis of the aniline MA4-044 wasprepared according to the method shown in Scheme 4D. In this way3,5-dinitroaniline was acetylated and reduced with hydrazine hydrate andpalladium on carbon (Gunawan, et al., Construction of functionalizedtricyclic dihydropyrazino-quinazolinedione chemotypes via anUgi/N-acyliminium ion cyclization cascade. Tet. Lett. 2013, 54,4467-4470) to give MA4-042. Sulfonylation of MA4-042 followed byhydrolysis of the acetamide gives the A-ring aniline MA4-044.

The B-ring anilines were synthesized according to the routes shown inSchemes 5 (Tangallapally, et al., Synthesis and evaluation of cyclicsecondary amine substituted phenyl and benzyl nitrofuranyl amides asnovel antituberculosis agents. J Med Chem 2005, 48, 8261-9;WO2011/120026; U.S. Pat. No. 8,563,542).

Example 2: Synthesis of the Pyrimidine-A-Ring Intermediates 3

Procedure A:

A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.) andsubstituted aniline (1.15 equiv.) in MeOH/water (1:1.5, 0.2 M) wasstirred at 45° C. The reaction time is indicated below. Upon cooling toambient temperature, the desired product precipitated and was filtered,washed with MeOH/water (1:1.5, 20 mL), and dried.

Procedure B:

A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), andsubstituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) inisopropanol (0.1 M) was stirred and heated at reflux. The reaction time,work-up, and product isolation procedure are described below.

2,5-Dichloro-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)pyrimidin-4-amine(SG1-149)

This was prepared from 2,4,5-trichloropyrimidine (0.100 g) and SG1-137(0.031 g) using procedure A (reaction time, 21 h) to give the titlecompound as a white solid (0.190 g, 93%). Mp: 172-173° C. ¹H NMR (400MHz, DMSO-d₆): δ 9.79 (s, 1H, disappeared on D₂O shake), 8.42 (s, 1H),8.07 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.64-7.52 (m, 3H; 1H disappearedon D₂O shake), 1.11 (s, 9H). HPLC-MS (ESI+): m/z 773.1 [30%,(M³⁵Cl³⁵Cl+M³⁵Cl³⁷Cl+Na)⁺], 377.1 [70%, (M³⁵Cl³⁷Cl+H)⁺], 375.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(4-chloro-3-methoxyphenyl)pyrimidin-4-amine (SG1-168)

This was prepared from 2,4,5-trichloropyrimidine (0.500 g),4-chloro-3-methoxyaniline (0.451 g), and DIPEA (0.570 mL) usingprocedure B (reaction time, 12 h). The solvent was removed and EtOAc (20mL) was added. The organic layer was extracted with water (20 mL). Theaqueous layer was re-extracted with EtOAc (20 mL). The organic layerswere combined and washed with water and brine (20 mL each), dried(Na₂SO₄) and concentrated under reduced pressure. The resulting darkpurple oil was triturated using EtOAc/hexanes to give the title compoundas a light purple solid (0.680 g, 82%). Mp: 136-138° C. ¹H NMR (400 MHz,DMSO-d₆): δ 9.57 (s, 1H, disappeared on D₂O shake), 8.41 (s, 1H), 7.49(d, J=2.2 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.28 (dd, J=8.6, 2.2 Hz, 1H),3.82 (s, 3H). HPLC-MS (ESI+): m/z 308.1 [40%, (M³⁵Cl³⁷Cl³⁷Cl+H)⁺], 306.1[98%, (M³⁵Cl³⁵Cl³⁷Cl+H)⁺], 304.0 [100%, (M³⁵Cl³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-3-methoxyphenyl)-5-methylpyrimidin-4-amine(SG1-173-01)

This was prepared from 2,4-dichloro-5-methylpyrimidine (1.00 g),4-chloro-3-methoxyaniline (1.02 g), and DIPEA (1.28 mL) using procedureB (reaction time, 13 h). The solvent was removed and EtOAc (40 mL) wasadded. The organic layer was extracted with water (40 mL). The aqueouslayer was re-extracted with EtOAc (40 mL). The organic layers werecombined, washed with water and brine (40 mL each), dried (Na₂SO₄), andconcentrated under reduced pressure. The resulting residue was purifiedvia column chromatography (SiO₂) eluting with hexanes/EtOAc (0:10 to 4:6v/v) to give the title compound as an off-white solid (0.530 g, 30%).Mp: 132-134° C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.90 (s, 1H, disappeared onD₂O shake), 8.07 (s, 1H), 7.54 (s, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.33 (d,J=8.7 Hz, 1H), 3.83 (s, 3H), 2.16 (s, 3H). HPLC-MS (ESI+): m/z 286.1[70%, (M³⁵Cl³⁷Cl+H)⁻], 284.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(3-tert-butylphenyl)pyrimidin-4-amine (SG1-175)

A solution of 2,4,5-trichloropyrimidine (1.00 g), 3-(tert-butyl)aniline(0.813 mg), and DIPEA (5.70 mL) in EtOH (5 mL) was heated at reflux for14 h. The mixture was concentrated under reduced pressure. The residuewas dissolved in EtOAc (50 mL) and washed with water (2×50 mL) and brine(50 mL). The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure to give the title compound as a brown solid (1.545 g,96%). Mp: 107-110° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.48 (s, 1H,disappeared on D₂O shake), 8.35 (s, 1H), 7.62 (t, J=1.9 Hz, 1H), 7.41(ddd, J=7.8, 1.9, 1.0 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.19 (ddd, J=7.8,1.9, 1.0 Hz, 1H), 1.27 (s, 9H). HPLC-MS (ESI+): m/z 300.1 [10%,(M³⁷Cl³⁷Cl+H)⁻], 298.1 [65%, (M³⁵Cl³⁷Cl+H)⁺], 296.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(4-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)pyrimidin-4-amine(SG1-182)

This was prepared from 2,4,5-trichloropyrimidine (0.500 g) and SG1-177(0.715 g) using procedure A (stirred for 4 d). The crude solid waspurified via flash chromatography (SiO₂) eluting with hexanes/EtOAc(0:10 to 4:6 v/v) to provide the title compound as a tangerine-coloredsolid (0.590 g, 58%). Mp: 180-181° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.73(s, 1H, disappeared on D₂O shake), 8.46 (s, 1H), 7.80 (s, 4H), 7.48 (s,1H, disappeared on D₂O shake), 1.09 (s, 9H). HPLC-MS (ESI+): m/z 773.1[10%, (MCl³⁵Cl³⁷+M³⁵Cl³⁵Cl+Na)], 379.1 [10%, (MCl³⁷Cl³⁷+H)⁺], 377.1[70%, (MCl³⁵Cl³⁷+H)⁺], 375.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(3-[N-(methylethyl)sulfamoyl]phenyl)pyrimidin-4-amine(SG2-003)

This was prepared from 2,4,5-trichloropyrimidine (0.550 g) and SG1-147(0.740 g) using procedure A (reaction time, 22.5 h) to give the titlecompound as a white solid (0.948 g, 88%). Mp: 153-155° C. ¹H NMR (400MHz, DMSO-d₆): δ 9.79 (s, 1H, disappeared on D₂O shake), 8.42 (s, 1H),8.07 (s, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.62-7.53 (m, 3H; 1H, disappearedon D₂O shake), 3.30 (septet, J=6.6 Hz, 1H), 0.95 (d, J=6.6 Hz, 6H).HPLC-MS (ESI+): m/z 745.0 [10%, (MCl³⁵Cl³⁷+M³⁵Cl³⁵Cl+Na)⁺], 365.0 [15%,(M³⁷Cl³⁷Cl+H)⁺], 363.0 [75%, (M³⁵Cl³⁷Cl+H)⁺], 361.0 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-5-methylpyrimidin-4-amine(SG2-007)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.500 g) andSG1-177 (0.805 g) using procedure A (reaction time, 22.5 h). Theresulting residue was purified via column chromatography (SiO₂) elutingwith hexanes/EtOAc (3:7 to 5:5 v/v) to give the title compound as anoff-white solid (0.541 g, 50%). Mp: 281° C. (dec). ¹H NMR (400 MHz,DMSO-d₆): δ 9.07 (s, 1H, disappeared on D₂O shake), 8.13 (s, 1H), 7.85(d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.42 (s, 1H, disappeared onD₂O shake), 2.19 (s, 3H), 1.08 (s, 9H). HPLC-MS (ESI+): m/z 731.1 [10%,(2M³⁵Cl+H)⁺], 357.1 [40%, (M³⁷Cl+H)⁺], 355.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-[3-(1,1-dimethylethyl)phenyl]-5-methylpyrimidin-4-amine(SG2-013)

A solution of 2,4-dichloro-5-methylpyrimidine (0.500 g),3-(tert-butyl)aniline (0.458 mg), and DIPEA (3.21 mL) in EtOH (2.5 mL)was heated at reflux for 24 h. The mixture was concentrated underreduced pressure. The resulting residue was dissolved in EtOAc (25 mL),washed with water (2×25 mL) and brine (25 mL). The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure to give the titlecompound as an off-white solid (0.564 g, 67%). Mp: 174-175° C. ¹H NMR(400 MHz, DMSO-d₆): δ 8.80 (s, 1H, reduced by 50% on D₂O shake), 8.01(s, 1H), 7.65 (t, J=1.9 Hz, 1H), 7.47 (ddd, J=7.8, 1.9, 1.0 Hz, 1H),7.26 (t, J=7.8 Hz, 1H), 7.12 (ddd, J=7.8, 1.9, 1.0 Hz, 1H), 2.15 (s,3H), 1.27 (s, 9H). HPLC-MS (ESI+): m/z 278.1 [40%, (M³⁷Cl+H)⁺], 276.1[100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[N-(methylethyl)sulfamoyl]phenyl)-5-methylpyrimidin-4-amine(SG2-014)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.500 g) andSG1-147 (0.755 g) using procedure A (reaction time, 10 d) to give thetitle compound as an off-white solid (0.600 g, 57%). Mp: 192-194° C. ¹HNMR (400 MHz, DMSO-d₆): δ 9.12 (s, 1H, disappeared on D₂O shake), 8.10(t, J=1.8 Hz, 1H, coupling visible upon D₂O shake), 8.06 (d, J=0.8 Hz,1H, coupling visible upon D₂O shake), 7.92 (ddd, J=7.9, 1.8, 1.0 Hz,1H), 7.57 (d, J=6.8 Hz, 1H, disappeared on D₂O shake), 7.56 (t, J=7.9Hz, 1H), 7.49 (dt, J=7.9, 1.8 Hz, 1H), 3.28 (septet, J=6.8 Hz, 1H), 2.17(s, 3H), 0.95 (d, J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z 681.2 [10%,(2M³⁵Cl+H)⁺], 343.1 [40%, (M³⁷Cl+H)⁻]. 341.1 [100%, (M³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine (SG2-047)

This was prepared from 2,4,5-trichloropyrimidine (0.367 g),3,4,5-trimethoxyaniline (0.385 g), and DIPEA (0.420 mL) using procedureB (reaction time, 14 h). The precipitate filtered and washed with water(2×10 mL), hexanes (2×10 mL), and dried to give the title compound as anoff-white solid (0.642 g, 97%). Mp: 236° C. (dec). ¹H NMR (400 MHz,DMSO-d₆): δ 9.41 (s, 1H, disappeared on D₂O shake), 8.36 (s, 1H), 7.04(s, 2H), 3.75 (s, 6H), 3.64 (s, 3H). HPLC-MS (ESI+): m/z 681.1 [40%,(M³⁵Cl+M³⁷Cl+Na)⁺], 332.1 [60%, (M³⁵Cl³⁷Cl+H)⁺], 330.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-amine(SG2-048)

This was prepared from 2,4,5-trichloropyrimidine (0.367 g),2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.318 g), and DIPEA (0.420 mL)using procedure B (reaction time, 14 h). The solvent was removed andEtOAc (20 mL) was added. The organic layer was washed with water (20mL). The aqueous layer was re-extracted with EtOAc (20 mL). The organiclayers were combined and washed with water and brine (20 mL each), dried(Na₂SO₄), and concentrated under reduced pressure to give the titlecompound as a dark brown oil (0.635 g, 107%, 90% purity based on ¹HNMR), which was used for the next step without purification. ¹H NMR (400MHz, DMSO-d₆): δ 9.36 (s, 1H, disappeared on D₂O shake), 8.31 (s, 1H),7.10 (d, J=2.5 Hz, 1H), 6.98 (dd, J=8.7, 2.5 Hz, 1H), 6.84 (d, J=8.7 Hz,1H), 4.23 (s, 4H). HPLC-MS (ESI+): m/z 300.1 [70%, (M³⁵Cl³⁷Cl+H)⁺],298.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(Benzo[d][1,3]dioxol-5-yl)pyrimidin-4-amine (SG2-049)

This was prepared from 2,4,5-trichloropyrimidine (0.367 g),benzo[d][1,3]dioxol-5-amine (0.288 g), and DIPEA (0.420 mL) usingprocedure B (reaction time, 14 h). The mixture was concentrated underreduced pressure. The resulting solid was washed with water (3×10 mL),hexanes (1×10 mL), water (1×10 mL), and dried to give the title compoundas a brown solid (0.642 g, 97%). Mp: 197° C. (dec). ¹H NMR (400 MHz,DMSO-d₆): δ 9.43 (s, 1H, disappeared on D₂O shake), 8.31 (s, 1H), 7.13(s, 1H), 6.98-6.87 (m, 2H), 6.03 (s, 2H). HPLC-MS (ESI+): m/z 286.1[70%, (M³⁵Cl³⁷Cl+H)⁺], 284.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(3,4,5-trimethoxyphenyl)-5-methylpyrimidin-4-amine (SG2-050)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g),3,4,5-trimethoxyaniline (0.385 g), and DIPEA (0.420 mL) using procedureB (reaction time, 14 h). The mixture was concentrated under reducedpressure. The resulting solid was washed with MeOH (1×5 mL), water (2×10mL), hexanes (1×10 mL), and dried to give the title compound as anoff-white solid (0.360 g, 58%). Mp: 222° C. (dec). ¹H NMR (400 MHz,DMSO-d₆): δ 8.75 (s, 1H, reduced by 70% on D₂O shake), 8.02 (d, J=0.7Hz, 1H), 7.09 (s, 2H), 3.75 (s, 6H), 3.63 (s, 3H), 2.14 (s, 3H). HPLC-MS(ESI+): m/z 312.2 [20%, (M³⁷Cl+H)⁺], 310.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-4-amine(SG2-051)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g),2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.318 g), and DIPEA (0.420 mL)using procedure B (reaction time, 14 h). The solvent was removed andEtOAc (20 mL) was added. The organic layer was extracted with water (20mL). The aqueous layer was re-extracted with EtOAc (20 mL). The organiclayers were combined and washed with water and brine (20 mL each), dried(Na₂SO₄), concentrated under reduced pressure to give the title compoundas a dark brown oil (0.590 g, 106%, 90% purity based on ¹H NMR), whichwas used for the next step without purification. ¹H NMR (400 MHz,DMSO-d₆): δ 8.68 (s, 1H, disappeared on D₂O shake), 7.96 (d, J=0.9 Hz,1H), 7.18 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d,J=8.7 Hz, 1H), 4.34-4.15 (m, 4H), 2.10 (s, 3H). HPLC-MS (ESI+): m/z280.1 [30%, (M³⁷Cl+H)⁺], 278.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(Benzo[d][1,3]dioxol-5-yl)-5-methylpyrimidin-4-amine(SG2-052)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g),benzo[d][1,3]dioxol-5-amine (0.288 g), and DIPEA (0.420 mL) usingprocedure B (reaction time, 14 h). The solvent was removed. The solidobtained was poured into water/MeOH (10:1, 20 mL) and the mixture wassonicated. The precipitate filtered and washed with water (3×10 mL),hexanes (1×10 mL), water (1×10 mL), then dried to give the titlecompound as a dark grey solid (0.425 g, 81%). Mp: 134° C. (dec). ¹H NMR(400 MHz, DMSO-d₆): δ 8.76 (s, 1H, disappeared on D₂O shake), 7.97 (s,J=0.9 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 6.97 (dd, J=8.4, 2.1 Hz, 1H),6.89 (d, J=8.4 Hz, 1H), 6.01 (s, 2H), 2.11 (d, J=0.7 Hz, 3H). HPLC-MS(ESI+): m/z 266.1 [40%, (M³⁷Cl+H)⁺], 264.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-3-methoxyphenyl)-6-methylpyrimidin-4-amine(SG2-053-01)

This was prepared from 2,4-dichloro-6-methylpyrimidine (0.326 g),4-chloro-3-methoxyaniline (0.331 mg), and DIPEA (0.420 mL) usingprocedure B (reaction time, 3 d). Ethyl acetate (15 mL) was added to themixture which was then washed with water (15 mL). The aqueous layer wasre-extracted with EtOAc (15 mL). The organic layers were combined,washed with water and brine (15 mL each), dried (Na₂SO₄), andconcentrated under reduced pressure. The resulting residue was purifiedvia column chromatography (SiO₂) eluting with hexanes/EtOAc (2:8 to 3:4v/v) to give the title compound as an off-white solid (0.334 g, 59%).Mp: 168-169° C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.02 (s, 1H, disappearedon D₂O shake), 7.44 (d, J=1.7 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.17 (dd,J=8.6, 1.7 Hz, 1H), 6.59 (s, 1H), 3.83 (s, 3H), 2.28 (s, 3H). HPLC-MS(ESI+): m/z 286.1 [70%, (M³⁵Cl³⁷Cl+H)⁺], 284.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(4-chloro-2,5-dimethoxyphenyl)pyrimidin-4-amine(SG2-059)

This was prepared from 2,4,5-trichloropyrimidine (0.367 g),4-chloro-2,5-dimethoxyaniline (0.394 g), and DIPEA (0.420 mL) usingprocedure B (reaction time, 14 h). The precipitate was filtered, washedwith isopropanol (2×10 mL), water (2×10 mL), hexanes (1×10 mL), anddried to give the title compound as an off-white solid (0.622 g, 93%).Mp: 195-198° C. ¹H NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H), 8.21 (s, 1H),8.09 (s, 1H, disappeared on D₂O shake), 6.95 (s, 1H), 3.95 (s, 3H), 3.91(s, 3H). HPLC-MS (ESI+): m/z 338.0 [30%, (M³⁵Cl³⁷Cl³⁷Cl+H)⁺]. 336.0[90%, (M³⁵Cl³⁵Cl³⁷Cl+H)⁺], 334.0 [100%, (M³⁵Cl³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(4-chloro-3,5-dimethoxyphenyl)pyrimidin-4-amine(SG2-066)

This was prepared from 2,4,5-trichloropyrimidine (0.183 g), SG2-062-01(0.197 g), and DIPEA (0.210 mL) using procedure B (reaction time, 14.5h). The precipitate was filtered, washed with isopropanol (1×10 mL),water (2×10 mL), isopropanol (1×10 mL), hexanes (1×10 mL), and dried togive the title compound as an off-white solid (0.315 g, 94%). Mp: 252°C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.55 (s, 1H, disappeared on D₂Oshake), 8.42 (s, 1H), 7.23 (s, 2H), 3.81 (s, 6H). HPLC-MS (ESI+): m/z356.0 [40%, (M³⁵Cl³⁵C₃ ⁵Cl+Na)⁺], 338.0 [30%, (MCl³⁵Cl³⁷Cl³⁷+H)⁺], 336.0[95%, (M³⁵Cl³⁵Cl³⁷Cl+H)⁺], 334.1 [100%, (M³⁵Cl³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-3,5-dimethoxyphenyl)-5-methylpyrimidin-4-amine(SG2-067)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.163 g),SG2-062-01 (0.197 g), and DIPEA (0.210 mL) using procedure B (reactiontime, 1.5 d). The precipitate was filtered, washed with isopropanol(1×10 mL), water (2×10 mL), isopropanol (1×10 mL), hexanes (1×10 mL),and dried to give the title compound as a white solid (0.174 g, 55%).Mp: 237-238° C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.89 (s, 1H, disappeared onD₂O shake), 8.08 (s, 1H), 7.29 (s, 2H), 3.81 (s, 6H), 2.17 (s, 3H).HPLC-MS (ESI+): m/z 316.1 [60%, (M³⁵Cl³⁷Cl+H)⁺], 314.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-2,5-dimethoxyphenyl)-5-methylpyrimidin-4-amine(SG2-068)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g),4-chloro-2,5-dimethoxyaniline (0.394 g), and DIPEA (0.420 mL) usingprocedure B (reaction time, 5 d). The precipitate was filtered, washedwith isopropanol (1×10 mL), water (2×10 mL), isopropanol (1×10 mL),hexanes (1×10 mL), and dried to give the title compound as an off-whitesolid (0.284 g, 45%). Mp: 184-185° C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.44(s, 1H, disappeared on D₂O shake), 8.01 (s, 1H), 7.46 (s, 1H), 7.21 (s,1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.12 (s, 3H). HPLC-MS (ESI+): m/z 316.1[60%, (M³⁵Cl³⁷Cl+H)⁺], 314.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴(3-[N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl]phenyl)-pyrimidin-4-amine(SG2-082)

This was prepared from 2,4,5-trichloropyrimidine (0.183 g) and SG2-079(0.281 g) using procedure A (reaction time, 16 h) to give the titlecompound as a white solid (0.318 g, 81%). Mp: 183-186° C. ¹H NMR (400MHz, DMSO-d₆): δ 9.78 (s, 1H, disappeared on D₂O shake), 8.42 (s, 1H),8.06 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.56 (t,J=7.9 Hz, 1H), 7.33 (s, 1H, disappeared on D₂O shake), 4.75 (t, J=5.8Hz, 1H, disappeared on D₂O shake), 3.20 (d, J=5.8 Hz, 2H), 1.03 (s, 6H).HPLC-MS (ESI+): m/z 805.1 [50%, (M³⁵Cl³⁵Cl+M³⁵Cl³⁷Cl+Na)⁺], 803.1 [30%,(2M³⁵Cl³⁵Cl+Na)⁺], 413.0 [30%, (M³⁵Cl³⁵Cl+Na)⁺], 393.1 [60%,(M³⁵Cl³⁷Cl+H)⁺], 391.1 [100% o (M³⁵Cl³⁵Cl+H)⁻].

2-Chloro-N⁴-(4-methyl-[3-(N-1,1-dimethylethyl)sulfamoyl]phenyl)quinazoline-4-amine(SG2-115)

This was prepared from MA2-028 (0.199 g), SG2-100 (0.218 g), and DIPEA(0.210 mL) using procedure B (reaction time, 15 min). Water (6 mL) wasadded and the precipitate filtered, washed with water (3×10 mL), hexanes(3×10 mL), and dried to give the title compound as a yellow solid (0.315g, 78%). Mp: 197-199° C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H,disappeared on D₂O shake), 8.56 (d, J=8.2 Hz, 1H), 8.30 (d, J=2.3 Hz,1H), 7.95 (dd, J=8.3, 2.3 Hz, 1H), 7.88 (ddd, J=8.2, 7.0, 1.1 Hz, 1H),7.71 (dd, J=8.2, 1.1 Hz, 1H), 7.65 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.52(s, 1H, disappeared on D₂O shake), 7.41 (d, J=8.3 Hz, 1H), 2.57 (s, 3H),1.13 (s, 9H). HPLC-MS (ESI+): m/z 407.1 [30%, (M³⁷Cl+H)⁺], 405.1 [100%,(M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-5-carbamoylpyrimidin-4-amine(SG2-139-01)

This was prepared from SG2-138 (0.192 g) and SG1-137 (0.228 g) usingprocedure A (reaction time, 13.5 h). The resulting residue was purifiedvia column chromatography (SiO₂) eluting with hexanes/EtOAc (2:8 to 6:4v/v) to give the title compound as a white solid (0.105 g, 27%). Mp:243° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 11.65 (s, 1H, disappeared onD₂O shake), 8.80 (s, 1H), 8.47 (s, 1H, disappeared on D₂O shake), 8.10(s, 1H), 8.01 (s, 1H, disappeared on D₂O shake), 7.83-7.75 (m, 1H),7.59-7.53 (m, 3H; 1H disappeared on D₂O shake), 1.11 (s, 9H). HPLC-MS(ESI+): m/z 769.1 [40%, (2M³⁷Cl+H)⁺], 767.1 [100%, (2M³⁵Cl+H)⁺], 386.1[40%, (M³⁷Cl+H)⁺], 384.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-[3-(Cyclopropanesulfonamido)phenyl]-5-carboxamoylpyrimidin-4-amine(SG2-140-01)

This was prepared from SG2-138 (0.192 g) and RJ1-025 (0.212 g) usingprocedure A (reaction time, 13.5 h). The resulting residue was purifiedvia column chromatography (SiO₂) eluting with hexanes/EtOAc (3:7 to 5:5v/v) to give the title compound as an off-white solid (0.097 g, 26%).Mp: 239° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 11.52 (s, 1H,disappeared on D₂O shake), 9.84 (s, 1H, disappeared on D₂O shake), 8.77(s, 1H), 8.44 (s, 1H, disappeared on D₂O shake), 7.97 (s, 1H,disappeared on D₂O shake), 7.55 (s, 1H), 7.40-7.21 (m, 2H), 7.03-6.95(m, 1H), 2.71-2.63 (m, 1H), 1.02-0.90 (m, 4H). HPLC-MS (ESI+): m/z 737.1[20%, (M³⁷Cl+M³⁵Cl+H)⁺], 735.1 [30%, (2M³⁵Cl+H)⁺], 370.1 [40%,(M³⁷Cl+H)⁺], 368.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-[4-chloro-3-(cyclopropanesulfonamido)phenyl]-5-methyl-pyrimidin-4-amine(SG2-163)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.082 g),SG2-159 (0.123 g), and DIPEA (0.210 mL) using procedure B (reactiontime, 22.5 h). Water (10 mL) was added and the precipitate filtered,washed with water (3×10 mL), hexanes (1×10 mL), and dried to give thetitle compound as an off-white solid (0.099 g, 53%). Mp: 218-219° C. ¹HNMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H, disappeared on D₂O shake), 9.00(s, 1H, disappeared on D₂O shake), 8.08 (d, J=0.8 Hz, 1H), 7.86 (d,J=2.5 Hz, 1H), 7.57 (dd, J=8.8, 2.5 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H),2.75-2.65 (m, 1H), 2.16 (s, 3H), 1.04-0.90 (m, 4H). HPLC-MS (ESI+): m/z375.1 [70%, (M³⁵Cl³⁷Cl+H)⁺], 373.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-[4-chloro-3-(cyclopropanesulfonamido)phenyl]-quinazoline-4-amine(SG2-164)

This was prepared from MA2-028 (0.099 g), SG2-159 (0.123 g), and DIPEA(0.210 mL) using procedure B (reaction time, 14 h). Water (5 mL) wasadded and the precipitate filtered and washed with water (3×10 mL),hexanes (1×10 mL), and dried to give the title compound as a yellowsolid (0.125 g, 61%). Mp: 253-256° C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.31(s, 1H, disappeared on D₂O shake), 9.54 (s, 1H, disappeared on D₂Oshake), 8.57 (d, J=8.5 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H), 7.90 (ddd,J=8.4, 7.1, 1.5 Hz, 1H), 7.76 (dd, J=8.4, 1.5 Hz, 1H), 7.73 (dd, J=8.4,1.5 Hz, 1H), 7.66 (ddd, J=8.4, 7.1, 1.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H),2.78-2.69 (m, 1H), 1.06-0.91 (m, 4H). HPLC-MS (ESI+): m/z 411.1 [70%,(M³⁵Cl³⁷Cl+H)⁺], 409.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-[4-Chloro-3-(cyclopropanesulfonamido)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine(SG2-165)

This was prepared from MA2-092 (0.095 g), SG2-159 (0.123 g), and DIPEA(0.210 mL) using procedure B (reaction time, 1.5 d). Water (5 mL) wasadded and the precipitate filtered, washed with water (3×10 mL), hexanes(1×10 mL), and dried to give the title compound as a light brown solid(0.099 g, 50%). Mp: 237° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.45(brs, 1H, disappeared on D₂O shake), 9.27 (s, 1H, disappeared on D₂Oshake), 7.87 (d, J=2.4 Hz, 1H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 7.46 (d,J=8.8 Hz, 1H), 2.80 (t, J=7.6 Hz, 4H), 2.74-2.64 (m, 1H), 2.05 (quintet,J=7.6 Hz, 2H), 1.02-0.89 (m, 4H). HPLC-MS (ESI+): m/z 401.1 [60%,(M³⁵Cl³⁷Cl+H)⁺], 399.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-[4-chloro-3-(cyclopropanesulfonamido)phenyl]-(5,7-dihydrofuro[3,4-d]pyrimidine-4-amine)(SG2-166)

This was prepared from MA2-096 (0.095 g), SG2-159 (0.123 g), and DIPEA(0.210 mL) using procedure B (reaction time, 14 h). Water (5 mL) wasadded and the precipitate filtered, washed with water (3×10 mL), hexanes(1×10 mL), and dried to give the title compound as a light brown solid(0.160 g, 80%). Mp: 252° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.69 (s,1H, disappeared on D₂O shake), 9.49 (s, 1H, disappeared on D₂O shake),7.82 (d, J=2.5 Hz, 1H), 7.61 (dd, J=8.8, 2.5 Hz, 1H), 7.50 (d, J=8.8 Hz,1H), 4.98 (s, 2H), 4.84 (s, 2H), 2.73-2.63 (m, 1H), 1.05-0.86 (m, 4H).HPLC-MS (ESI−) m/z 401.0 [70%, (M³⁵Cl³⁷Cl—H)⁺], 399.0 [100%,(M³⁵Cl³⁵Cl—H)⁺].

2-Chloro-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-5-methylpyrimidin-4-amine(SG3-012)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.082 g),SG3-105 (0.131 g), and DIPEA (0.210 mL) using procedure B (reactiontime, 20 h at reflux, 1.5 d at 120° C.). Water (5 mL) was added and theprecipitate filtered, washed with water (2×5 mL), hexanes (2×5 mL), anddried to give the title compound as a light brown solid (0.101 g, 52%).Mp: 274° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (s, 1H, disappearedon D₂O shake), 8.99 (s, 1H, disappeared on D₂O shake), 8.07 (s, 1H),7.92 (d, J=2.4 Hz, 1H), 7.56 (brd, J=8.7 Hz, 1H), 7.44 (d, J=8.7 Hz,1H), 2.16 (s, 3H), 1.32 (s, 9H). HPLC-MS (ESI+): m/z 391.1 [70%,(M³⁵Cl³⁷Cl+H)⁻], 389.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-([3-(N,N-dimethylsulfamoylamino)]phenyl)-5-methylpyrimidin-4-amine(SG3-038)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.163 g), SG3-033-01(0.215 g), and DIPEA (0.420 mL) in isopropanol (1 mL) was stirred andheated at reflux for 3 d. The solvent was removed and the resulting oilwas purified via column chromatography (SiO₂) eluting with hexanes/EtOAc(3:7 to 6:4 v/v) to give the title compound as a brown solid (0.172 g,50%). Mp: 270° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.85 (brs, 1H,disappeared on D₂O shake), 8.85 (s, 1H, disappeared on D₂O shake), 8.03(s, 1H), 7.52 (s, 1H), 7.31-7.18 (m, 2H), 6.93 (dt, J=6.8, 2.1 Hz, 1H),2.71 (s, 6H), 2.15 (s, 3H). HPLC-MS (ESI+): m/z 344.1 [40%, (M³⁷Cl+H)⁺],342.2 [100%, (M³⁵C+H)⁺].

2-Chloro-N⁴-[3-(1,1-dimethylethylsulfonamido)phenyl]-5-methylpyrimidin-4-amine(SG3-053)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.326 g), MA2-010 (0.457g), and DIPEA (0.836 mL) in isopropanol (2 mL) was stirred and heated atreflux for 3 d. The solvent was removed and the resulting oil waspurified via column chromatography (SiO₂) eluting with hexanes/EtOAc(1:9 to 1:1 v/v) to give the title compound as a brown solid (0.420 g,59%). Mp: 258° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.66 (s, 1H,reduced by 70% on D₂O shake), 8.88 (s, reduced by 50% on D₂O shake),8.03 (d, J=0.9 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.26 (dt, J=8.0, 1.8 Hz,1H), 7.22 (t, J=8.0 Hz, 1H), 6.99 (dt, J=8.0, 1.8 Hz, 1H), 2.14 (s, 3H),1.28 (s, 9H). HPLC-MS (ESI+): m/z 357.1 [40%, (M³⁷Cl+H)⁺], 355.1 [100%,(M³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-methyl-[3-(1,1-dimethylethylsulfonamido)]phenyl)-5-methylpyrimidin-4-amine(SG3-126)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.163 g), SG3-124 (0.242g), and DIPEA (0.420 mL) in isopropanol (1 mL) was stirred and heated at120° C. for 3.5 d. Water (5 mL) was added and the precipitate filtered,washed with water (2×10 mL), hexanes (2×10 mL), and dried to give thetitle compound as a yellow solid (0.297 g, 81%). Mp: 246° C. (dec). ¹HNMR (400 MHz, DMSO-d₆): δ 8.86 (s, 1H, disappeared on D₂O shake), 8.84(s, 1H, disappeared on D₂O shake), 8.01 (d, J=0.8 Hz, 1H), 7.73 (d,J=2.2 Hz, 1H), 7.34 (dd, J=8.3, 2.2 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H),2.30 (s, 3H), 2.14 (s, 3H), 1.32 (s, 9H). HPLC-MS (ESI+): m/z 759.3[10%, (2M³⁵Cl+Na)⁺], 371.2 [40%, (M³⁷Cl+H)⁺], 369.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-[3-(N-1,1-dimethylethyl)sulfamoyl]phenyl)-5-methylpyrimidin-4-amine(SG3-145)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.163 g), SG3-142-01(0.262 g), and DIPEA (0.420 mL) in isopropanol (1 mL) was stirred andheated at 120° C. for 3 d, 130° C. for 3 d, and 140° C. for 3 d. Thesolvent was removed and the resulting oil was purified via columnchromatography (SiO₂) eluting with hexanes/EtOAc (0:10 to 3:7 v/v) togive the title compound as a yellow solid (0.241 g, 62%). Mp: 282° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.19 (s, 1H, reduced by 50% on D₂Oshake), 8.34 (d, J=2.7 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H), 7.95 (dd, J=8.7,2.7 Hz, 1H), 7.66 (s, 1H, reduced by 40% on D₂O shake), 7.60 (d, J=8.7Hz, 1H), 2.17 (s, 3H), 1.12 (s, 9H). HPLC-MS (ESI+): m/z 779.1 [20%,(M³⁵Cl³⁷Cl+M³⁵Cl³⁵Cl+H)⁺], 391.1 [80%, (M³⁵Cl³⁷Cl+H)⁺], 389.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-3-nitrophenyl)-5-methylpyrimidin-4-amine (SG3-149)

A mixture of 2,4-dichloro-5-methylpyrimidine (4.00 g),4-chloro-3-nitroaniline (4.23 g), and DIPEA (10.26 mL) in isopropanol(12 mL) in a 10-mL Ace pressure tube was stirred and heated at 160° C.for 6 d. The solvent was removed and the resulting oil was purified viacolumn chromatography (SiO₂) eluting with hexanes/EtOAc (0:10 to 1:1v/v) to give the title compound as a yellow solid (3.623 g, 49%). Mp:251° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.28 (s, 1H, disappeared onD₂O shake), 8.47 (d, J=2.4 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J=8.8, 2.4Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 2.19 (s, 3H). HPLC-MS (ESI+): m/z 301.1[60%, (M³⁵Cl³⁷Cl+H)⁺], 299.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴(3-[N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl]phenyl)-5,6-dimethylpyrimidin-4-amine(SG2-084)

This was prepared from RJ1-008 (0.177 g) and SG2-079 (0.281 g) usingprocedure A (reaction time, 16 h at 80° C.) to give the title compoundas a white solid (0.318 g, 81%). The solvent was removed under reducedpressure and the resulting residue was purified via columnchromatography (SiO₂) eluting with hexanes/EtOAc (0:10 to 4:6 v/v) togive the title compound as an off-white solid (0.060 g, 16%; 78% puritybased on HPLC-MS) which was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆): 9.02 (s, 1H), 8.05 (s, 1H),7.88-7.80 (m, 2H), 7.51 (brs, 1H), 7.31 (s, 1H), 3.19 (d, J=2.9 Hz, 2H),2.33 (s, 3H), 2.16 (s, 3H), 1.15 (s, 6H). HPLC-MS (ESI+): m/z 387.2[35%, (M³⁷Cl+H)⁺], 385.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-methyl-[3-(N-1,1-dimethylethyl)sulfamoyl]phenyl)-5-methylpyrimidin-4-amine(SG2-108)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.163 g) andSG2-100 (0.279 g) using procedure A (reaction time; 17 h at 45° C., 2.5h at 80° C.) to give the title compound as an off-white solid (0.135 g,37%; 65% purity based on HPLC-MS) which was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (s, 1H),8.15 (d, J=2.3 Hz, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.76 (dd, J=8.3, 2.3 Hz,1H), 7.46 (s, 1H), 7.33 (d, J=8.3 Hz, 1H), 2.54 (s, 3H), 2.16 (s, 3H),1.11 (s, 9H). HPLC-MS (ESI+): m/z 737.3 [10%, (2M³⁵Cl+H)⁺], 371.2 [35%,(M³⁷Cl+H)⁺], 369.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-3-methoxyphenyl)-5-carbamoylpyrimidin-4-amine(SG2-132)

This was prepared from SG2-138 (0.096 g) and 4-chloro-3-methoxyaniline(0.079 g) using procedure B (reaction time, 12.5 h). Water (2 mL) wasadded and the precipitate was filtered, washed with water (1×10 mL) andhexanes (1×10 mL), and dried to give the title compound as a brown solid(0.110 g, 49%; 52% purity based on HPLC-MS) and used in the next stepwithout further purification. HPLC-MS (ESI+): m/z 315.0 [30%,(M³⁷Cl+H)⁺], 313.0 [40%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-[3-(ethylsulfonamido)]phenyl)-5-methylpyrimidin-4-amine(SG4-012)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.326 g), SG4-009 (0.469g), and DIPEA (0.836 mL) in isopropanol (1 mL) in a 2-mL microwave vialwas stirred and heated at 140° C. for 3 d. Water (50 mL) was added andthe precipitate was filtered, washed with water (2×50 mL) and hexanes(1×10 mL), and dried to give the title compound as an off-white solid(0.568 g, 79%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.42 (s, 1H, disappeared onD₂O shake), 9.00 (s, 1H, disappeared on D₂O shake), 8.08 (s, 1H), 7.81(d, J=1.7 Hz, 1H), 7.52 (d, J=8.6, 1.7 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H),3.18 (q, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.28 (t, J=7.3 Hz, 3H). HPLC-MS(ESI+): m/z 363.1 [80%, (M³⁵Cl³⁷Cl+H)⁺], 361.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-[3-(2-methylpropylsulfonamido)]phenyl)-5-methylpyrimidin-4-amine(SG4-018)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.081 g), SG4-016 (0.135g), and DIPEA (0.210 mL) in isopropanol (0.25 mL) in a 2-mL microwavevial was stirred and heated at 140° C. for 3 d. The solvent was removedand the resulting oil was purified via column chromatography (SiO₂)eluting with EtOAc/hexanes (1:9 to 4:6 v/v) to give the title compoundas an off-white solid (0.085 g, 44%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.46(s, 1H, disappeared on D₂O shake), 9.00 (s, 1H, reduced by 40% on D₂Oshake), 8.08 (d, J=0.8 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.8,2.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 3.06 (d, J=6.5 Hz, 2H), 2.25-2.12(m, 1H) overlapping 2.16 (s, 3H), 1.01 (d, J=6.5 Hz, 6H). HPLC-MS(ESI+): m/z 391.1 [80%, (M³⁵Cl³⁷Cl+H)⁺], 389.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

1-(tert-Butylsulfonyl)-N-(2-chloro-5-methylpyrimidin-4-yl)indolin-6-amine(SG4-024)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.163 g), SG4-020 (0.254g), and DIPEA (0.418 mL) in isopropanol (0.5 mL) in a 2-mL microwavevial was stirred and heated at 140° C. for 3 d. The solvent was removedand the resulting oil was purified via column chromatography (SiO₂)eluting with EtOAc/hexanes (0:10 to 4:6 v/v) to give the title compoundas an off-white foam (0.308 g, 81%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.85(s, 1H, disappeared on D₂O shake), 8.00 (s, 1H), 7.57 (d, J=1.7 Hz, 1H),7.17 (d, J=8.1 Hz, 1H), 7.10 (dd, J=8.1, 1.7 Hz, 1H), 4.05 (t, J=8.5 Hz,2H), 3.07 (t, J=8.5 Hz, 2H), 2.13 (s, 3H), 1.39 (s, 9H). HPLC-MS (ESI+):m/z 381.2 [35%, (M³⁵Cl+H)⁺].

1-(tert-butylsulfonyl)-N-(2-chloro-5-methylpyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-7-amine(SG4-026)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.163 g), SG4-023 (0.268g), and DIPEA (0.418 mL) in isopropanol (0.5 mL) in a 2-mL microwavevial was stirred and heated at 140° C. for 3 d. The solvent was removedand the resulting oil was purified via column chromatography (SiO₂)eluting with EtOAc/hexanes (0:10 to 4:6 v/v) to give the title compoundas a white foam (0.314 g, 80%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (s,1H, reduced by 70% on D₂O shake), 8.00 (d, J=0.9 Hz, 1H), 7.79 (d, J=2.1Hz, 1H), 7.14 (dd, J=8.3, 2.1 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 3.65(brs, 2H), 2.77 (t, J=6.7 Hz, 2H), 2.13 (d, J=0.8 Hz, 3H), 1.90(quintet, J=6.7 Hz, 2H), 1.43 (s, 9H). HPLC-MS (ESI+): m/z 397.2 [35%,(M³⁷Cl+H)⁺], 395.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(phenylbenzamide)-5-fluoropyrimidin-4-amine (SG3-071)

A mixture of 2,4-dichloro-5-fluoropyrimidine (0.167 g), SG3-063 (0.212g), and DIPEA (0.418 mL) in isopropanol (1 mL) was stirred and heated at85° C. for 3 d. The mixture was concentrated under reduced pressure. Theresulting oil was purified via column chromatography (SiO₂) eluting withEtOAc/hexanes (0:10 to 1:1 v/v) to give the title compound as a yellowsolid (0.262 g, 77%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.27 (s, 1H,disappeared on D₂O shake), 10.18 (s, 1H, reduced by 60% on D₂O shake),8.41 (d, J=3.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H),7.78 (d, J=7.6 Hz, 2H), 7.35 (d, J=7.6 Hz, 2H), 7.09 (t, J=7.64 Hz, 1H).¹⁹F NMR (376 MHz, DMSO-d₆): δ −152.79. HPLC-MS (ESI+): m/z 709.2 [80%,(M³⁷Cl³⁵Cl+H)⁺], 707.1 [80%, (2M³⁵Cl+H)⁺], 344.2 [35%, (M³⁷Cl+H)⁻],343.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(cyclopropylbenzamide)-5-fluoropyrimidin-4-amine (SG3-076)

A mixture of 2,4-dichloro-5-fluoropyrimidine (0.167 g), SG3-067 (0.176g), and DIPEA (0.418 mL) in isopropanol (1 mL) was stirred and heated at85° C. for 15 h. The mixture was concentrated under reduced pressure.The resulting oil was purified via column chromatography (SiO₂) elutingwith EtOAc/hexanes (0:10 to 1:1 v/v) to give the title compound as ayellow solid (0.205 g, 67%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H,disappeared on D₂O shake), 8.39 (d, J=3.4 Hz, 1H, reduced by 40% on D₂Oshake), 8.37 (d, J=4.2 Hz, 1H), 7.82 (d, J=8.9 Hz, 2H), 7.78 (d, J=8.9Hz, 2H), 2.88-2.78 (m, 1H), 0.74-0.65 (m, 2H), 0.59-0.52 (m, 2H). ¹⁹FNMR (376 MHz, DMSO-d₆): δ −152.93. HPLC-MS (ESI+): m/z 637.2 [20%,(M³⁷Cl³⁵Cl+Na)⁺], 635.2 [25%, (2M³⁵Cl+Na)⁺], 615.2 [20%,(M³⁷Cl³⁵Cl+H)⁺], 613.2 [25%, (2M³⁵Cl+H)⁺], 309.2 [35%, (M³⁷Cl+H)⁺],307.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(cyclopropylbenzamide)-5-methylpyrimidin-4-amine (SG3-083)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.163 g), SG3-067 (0.176g), and DIPEA (0.418 mL) in isopropanol (1 mL) was stirred and heated at120° C. for 3 d. Water (5 mL) was added and the precipitate filtered andwashed with water (1×10 mL), isopropanol (1×1 mL), hexanes (1×20 mL),then dried to give the title compound as a white solid (0.175 g, 58%).¹H NMR (400 MHz, DMSO-ds): δ 9.01 (s, 1H), 8.35 (d, J=4.1 Hz, 1H), 8.09(d, J=0.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H),2.86-2.76 (m, 1H), 2.17 (s, 3H), 0.704-.64 (m, 2H), 0.58-0.50 (m, 2H).HPLC-MS (ESI+): m/z 605.2 [25%, (2M³⁵Cl+H)⁺], 305.2 [35%, (M³⁷Cl+H)⁺],303.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chlorophenyl)-5-methylpyrimidin-4-amine (SG3-139)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.326 g), 4-chloroaniline(0.255 g), and DIPEA (0.836 mL) in isopropanol (2 mL) was stirred andheated at 120° C. for 3 d. The mixture was concentrated under reducedpressure. The resulting oil was purified via column chromatography(SiO₂) eluting with EtOAc/hexanes (0:10 to 3:7 v/v) to give the titlecompound as a light yellow solid (0.405 g, 80%). ¹H NMR (400 MHz,DMSO-d₆): δ 8.93 (s, 1H, disappeared on D₂O shake), 8.06 (s, 1H), 7.66(d, J=8.9 Hz, 2H), 7.41 (d, J=8.9 Hz, 2H), 2.15 (s, 3H). HPLC-MS (ESI+):m/z 256.1 [70%, (M³⁵Cl³⁷Cl+H)⁺], 254.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(3,4-dichlorophenyl)-5-methylpyrimidin-4-amine (SG3-140)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.326 g),3,4-dichloroaniline (0.324 g), and DIPEA (0.836 mL) in isopropanol (2mL) was stirred and heated at 120° C. for 3 d. The mixture wasconcentrated under reduced pressure. The resulting oil was purified viacolumn chromatography (SiO₂) eluting with EtOAc/hexanes (0:10 to 3:7v/v) to give the title compound as a light yellow solid (0.331 g, 57%).¹H NMR (400 MHz, CDCl₃): δ 9.01 (s, 1H, disappeared on D₂O shake), 8.11(s, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.71 (dd, J=8.8, 2.3 Hz, 1H), 7.61 (d,J=8.8 Hz, 1H), 2.16 (s, 3H). HPLC-MS (ESI+): m/z 290.0 [90%,(M³⁵Cl³⁵Cl³⁷Cl+H)⁺], 288.0 [100%, (M³⁵Cl³⁵Cl³⁵Cl+H)⁺].

N-tert-Butyl-3-(2-chloro-5,6-dimethylpyrimidin-4-ylamino)benzenesulfonamide(RJ1-010)

A mixture of RJ1-008 (0.500 g, 2.82 mmol),3-amino-N-tert-butylbenzenesulfonamide (SG1-137) (0.74 g, 3.24 mmol),MeOH (5 mL), and water (7.5 mL) was heated to reflux at 40° C. Thereflux temperature was raised to 80° C. and the reaction was furtherheated for 26 hours. Upon cooling to ambient temperature, theprecipitate which formed was then filtered and washed with water (50 mL)to yield RJ1-010 as an off-white solid (0.649 g, 62%). m.p.=232° C.(decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.05 (s, 1H),7.82-7.78 (m, 1H), 7.53-7.50 (m, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.11(s, 9H). LRMS (ESI+) m/z 369.2 (M³⁵Cl+H)⁺, 371.2 (M³⁷Cl+H); (ESI−) m/z367.2 (M³⁵Cl—H)⁻, 369.2 (M³⁷Cl—H)⁻; HRMS (ESI+) m/z calculated forC₁₆H₂₁ClN₄O₂S (M+H)⁺ 369.11465, found 369.11431.

2-Chloro-N-(4-chloro-3-methoxyphenyl)-5,6-dimethylpyrimidin-4-amine(RJ1-034)

A mixture of RJ1-008 (0.354 g, 2.0 mmol), 4-chloro-3-methoxyaniline(0.331 g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol), and iPrOH (2 mL) wasadded to a 5 mL microwave vial which was then scaled and placed in a hotoil bath at 85° C. with stirring. After 23.5 hours, DMAP (0.024 g, 0.2mmol) was added as no significant reaction was observed by TLC or LC/MS.After 3.5 days, the vial was removed from the oil bath and the reactionmixture was concentrated before being dissolved in EtOAc (20 mL) andwashed with water (20 mL). The aqueous layer was re-extracted with EtOAc(20 mL). The combined organic layers were washed with water (20 mL),brine (20 mL), dried over sodium sulfate, and concentrated. The residuewas then dissolved in EtOAc and purified via flash chromatography, andthe desired product was collected at hexane/EtOAc 22-25% to give RJ1-034as a yellow-orange solid (0.117 g, 20%). m.p.=162° C. (decomposed). ¹HNMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 7.49 (d, J=2.3 Hz, 1H), 7.35 (d,J=8.6 Hz, 1H), 7.28 (dd, J=8.6, 2.3 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H),2.14 (s, 3H). LRMS (ESI+) m/z 298.1 (M³⁵Cl+H)⁺, 300.0 (M³⁷Cl+H)⁺; HRMS(ESI+) m/z calculated for C₁₃H₁₃Cl₂N₃₀ (M+H)⁺ 298.05084, found298.04992.

2-Chloro-5,6-dimethyl-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine(RJ1-037)

A mixture of RJ1-008 (0.354 g, 2.0 mmol), 3,4,5-trimethoxyaniline (0.385g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol) and iPrOH (2 mL) was added to a5 mL microwave vial which was then sealed and placed in a hot oil bathat 85° C. with stirring for 3.5 days. At this point, a large amount ofyellow-white precipitate was observed in the vial so the reactionmixture was filtered and the solid washed with MeOH (2×10 mL) and water(10 mL) before being left to dry in vacuo to give RJ1-037 as anoff-white solid (0.232 g, 36%). m.p.=214-217° C. ¹H NMR (400 MHz,DMSO-d₆) δ 8.61 (s, 1H), 7.04 (s, 2H), 3.74 (s, 6H), 3.63 (s, 3H), 2.30(s, 3H), 2.12 (s, 3H). LRMS (ESI+) m/z 324.2 (M³⁵Cl+H)⁺, 326.2(M³⁷Cl+H); HRMS (ESI+) m/z calculated for C₁₅H₁₈ClN₃O₃ (M+H)⁺ 324.11095,found 324.11200.

2,5-Dichloro-N-(3-isopropoxyphenyl)pyrimidin-4-amine (RJ1-048)

A mixture of 2,4,5-trichloropyrimidine (0.367 g, 2.0 mmol),3-isopropoxyaniline (0.310 mL, 2.1 mmol), DIPEA (0.420 mL, 2.4 mmol),and iPrOH (2 mL) was added to a 5 mL microwave vial which was thensealed and placed in a hot oil bath with stirring at 85° C. for 1.5hours. MeOH was added and the reaction mixture was then evaporated underreduced pressure to give a whitish-yellow solid. This solid was thendissolved in EtOAc (20 mL) and washed with water (20 mL). The aqueouslayer was re-extracted with EtOAc (20 mL) and the combined organiclayers were washed with water (20 mL), brine (20 mL), dried over sodiumsulfate and concentrated to yield RJ1-048 as a caramel-colored product(0.521 g, 87%). m.p.=100° C. (decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ9.44 (s, 1H), 8.37 (s, 1H), 7.27-7.20 (m, 2H), 7.15-7.10 (m, 1H), 6.70(dd, J=8.1, 2.1 Hz, 1H), 4.63-4.44 (m, 1H), 1.27 (d, J=6.0 Hz, 6H). LRMS(ESI+) m/z 298.1 (MCl³⁵Cl³⁵+H), 300.1 (MCl³⁵Cl₃₇+H)⁺, 302.1(MCl³⁷Cl³⁷+H)⁺; (ESI−) m/z 296.0 (MCl³⁵Cl³⁵—H)⁻, 298.0 (MCl³⁵Cl³⁷—H)⁻,300.0 (MCl³⁷Cl³⁷—H). HRMS (ESI+) m/z calculated for C₁₃H₁₃Cl₂N₃₀ (M+H)⁺298.05084, found 298.05025.

N-(3-(2,5-Dichloropyrimidin-4-ylamino)phenyl)cyclopropanesulfonamide(RJ1-050)

A mixture of 2,4,5-trichloropyrimidine (0.200 g, 1.09 mmol),N-(3-aminophenyl)cyclopropanesulfonamide (RJ1-025) (0.266 g, 1.25 mmol),MeOH (2 mL), and water (3 mL) was added to a 5 mL microwave vial whichwas then sealed and placed in a hot oil bath with stirring at 45° C. for21 hours. At this point, the vial was removed and allowed to cool toambient temperature before the reaction mixture was filtered and washedwith a solution of MeOH (20 mL) and water (30 mL) to yield RJ1-050 as abeige solid product (0.273 g, 70%). m.p.=197° C. (decomposed). ¹H NMR(400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.60 (s, 1H), 8.38 (s, 1H), 7.52 (s,1H), 7.39-7.20 (m, 2H), 7.00 (d, J=6.8 Hz, 1H), 2.67 (s, 1H), 1.05-0.89(m, 4H). LRMS (ESI+) m/z 359.1 (MCl³⁵Cl³⁵+H)⁺, 361.1 (MCl³⁵Cl³⁷+H)⁺,363.1 (MCl³⁷Cl³⁷+H)⁺; (ESI−) m/z 357.1 (MCl³⁵Cl³⁵—H)⁻, 359.1(MCl³⁵Cl³⁷—H)⁻, 361.1 (MCl³⁷Cl³⁷—H)⁻; HRMS (ESI+) m/z calculated forC₁₃H₁₂Cl₂N₄O₂S (M+H)⁺ 359.01308, found 359.01276.

N-Cyclopropyl-3-(2,5-dichloropyrimidin-4-ylamino)benzenesulfonamide(RJ1-052)

A mixture of 2,4,5-trichloropyrimidine (0.100 g, 0.545 mmol),3-amino-N-cyclopropylbenzcnesulfonamide (RJ1-042) (0.133 g, 0.627 mmol),MeOH (1 mL), and water (1.5 mL) was allowed to react and worked upfollowing the same procedure used to make RJ1-050 to provide RJ1-052 asa white solid product (0.138 g, 70%). m.p.=185° C. (decomposed). ¹H NMR(400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 8.45 (s, 1H), 8.10 (m, 1H), 7.98 (d,J=2.1 Hz, 1H), 7.90-7.84 (m, 1H), 7.67-7.56 (m, 2H), 2.18 (dt, J=9.4,3.2 Hz, 1H), 0.49 (ddd, J=27.4, 9.5, 5.2 Hz, 4H). LRMS (ESI+) m/z 359.1(MCl³⁵Cl³⁵+H)⁺, 361.1 (MCl³⁵Cl³⁷+H)⁺, 363.1 (MCl³⁷Cl³⁷+H); (ESI−) m/z357.0 (MCl³⁵Cl³⁵—H)⁻, 359.0 (MCl³⁵Cl³⁷—H)⁻, 361.0 (MCl³⁷Cl³⁷—H)⁻; HRMS(ESI+) m/z calculated for C₁₃H₁₂Cl₂N₄O₂S (M+H)⁺ 359.01308, found359.01277.

3-(2-Chloro-5-methylpyrimidin-4-ylamino)-N-cyclopropylbenzenesulfonamide(RJ1-046)

A mixture of RJ1-042 (0.300 g, 1.41 mmol),2,4-dichloro-5-methylpyrimidine (0.200 g, 1.23 mmol), MeOH (2 mL), andwater (3 mL) was allowed to react and worked up following the sameprocedure used to make RJ1-050, with the exception that the reaction wasrun for 23 hours, to provide RJ1-046 as a yellow-white product (0.216 g,52%). m.p.=192° C. (decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (s,1H), 8.15-8.08 (m, 2H), 7.95 (d, J=6.1 Hz, 2H), 7.59 (t, J=7.9 Hz, 1H),7.51 (d, J=7.8 Hz, 1H), 2.28 (s, 1H), 2.18 (s, 3H), 0.46 (ddd, J=11.5,7.4, 4.7 Hz, 4H). LRMS (ESI+) m/z 339.1 (M³⁵Cl+H)⁺, 341.2 (M³⁷Cl+H)⁺;HRMS (ESI+) m/z calculated for C₁₄H₁₅ClN₄O₂S (M+H)⁺ 339.06770, found339.06769.

N-(3-(2-Chloro-5-methylpyrimidin-4-ylamino)phenyl)cyclopropanesulfonamide(RJ1-032)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.200 g, 1.23 mmol),RJ1-025 (0.300 g, 1.41 mmol), MeOH (2.0 mL) and water (3.0 mL) washeated to reflux overnight in a hot oil bath at 45° C. with stirring.The next day, the flask was removed and allowed to cool to ambienttemperature before being evaporated under reduced pressure. The residuewas dissolved in MeOH and the desired product collected via filtration,to provide RJ1-032 (0.200 g, 48%) as a white solid. m.p.=211° C.(decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.96 (s, 1H),8.05 (s, 1H), 7.57 (s, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.27 (t, J=8.0 Hz,1H), 6.94 (d, J=7.7 Hz, 1H), 2.71-2.62 (m, 1H), 2.16 (s, 3H), 1.01-0.82(m, 4H). LRMS (ESI+) m/z 339.1 (M+H)⁺; (ESI−) m/z 337.1 (M−H)⁻.

2-Chloro-N-(3-isopropoxyphenyl)-5-methylpyrimidin-4-amine (RJ1-058)

A mixture of 2,4-dichloro-5-methylpyrimidine (0.326 g, 2.0 mmol),3-isopropoxyaniline (0.310 mL, 2.1 mmol), DIPEA (0.420 mL, 2.4 mmol),and iPrOH (2 mL) was allowed to react and worked up following the sameprocedure used to make RJ1-048, with the exception that no MeOH wasadded before workup and that the reaction was run overnight for 19.5hours. The residue was then purified via flash chromatography, and thedesired product RJ1-058 was collected at hexanes/EtOAc 15-20% as a flakycaramel-colored solid (0.242 g, 44%). m.p.=127-128° C. ¹H NMR (400 MHz,DMSO-d₆) δ 8.76 (s, 1H), 8.03 (s, 1H), 7.30 (t, J=2.2 Hz, 1H), 7.25-7.13(m, 2H), 6.64 (ddd, J=8.0, 2.4, 1.1 Hz, 1H), 4.59-4.50 (m, 1H), 2.15 (d,J=0.6 Hz, 3H), 1.27 (d, J=6.0 Hz, 6H). LRMS (ESI+) m/z 278.1 (M³⁵Cl+H)⁺,280.1 (M³⁷Cl+H)⁻; HRMS (ESI+) m/z calculated for C₁₄H₁₆ClN₃₀ (M+H)⁺278.10547, found 278.10860.

Ethyl 2-chloro-4-(4-chloro-3-methoxyphenylamino)pyrimidine-5-carboxylate(RJ1-061)

A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (0.442 g, 2.0mmol), 4-chloro-3-methoxyaniline (0.331 g, 2.1 mmol), DIPEA (0.42 mL,2.4 mmol), and iPrOH (2 mL) was added to a 5 mL microwave vial which wasthen sealed and placed in a hot oil bath with stirring at 85° C.overnight for 17 hours. At this point, a brown solid had formed and thiswas then washed with iPrOH (10 mL), water (10 mL), iPrOH (10 mL), andhexanes (10 mL) to yield RJ1-061 as a brown solid (0.570 g, 83%).m.p.=119° C. (decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H),8.81 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.28 (dd,J=8.6, 2.3 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.85 (s, 3H), 1.34 (t, J=7.1Hz, 3H). LRMS (ESI+) m/z 342.1 (MCl³⁵Cl³⁵+H)⁺, 344.0 (MCl³⁵Cl³⁷+H),346.0 (MCl³⁷Cl³⁷+H); (ESI−) m/z 339.3 (MCl³⁵Cl³⁵—H)⁻; HRMS (ESI+) m/zcalculated for C₁₄H₁₃Cl₂N₃O₃ (M+H)⁺ 342.04067, found 342.04100.

Ethyl4-(3-(N-tert-butylsulfamoyl)phenylamino)-2-chloropyrimidine-5-carboxylate(RJ1-063-01)

A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (0.221 g, 1.0mmol), 3-amino-N-tert-butylbenzenesulfonamide SG1-137 (0.265 g, 1.15mmol), MeOH (2 mL), and water (3 mL) was reacted and worked up followingthe same procedure used to make RJ1-050, with the exception that thereaction was run for 17 hours, to yield a tan solid. The solid was thenpurified via flash chromatography eluting with hexanes/EtOAc to provideRJ1-063-01 as a white flaky solid (0.211 g, 51%). m.p.=161° C.(decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.82 (s, 1H),8.11 (t, J=1.9 Hz, 1H), 7.80-7.72 (m, 1H), 7.63 (dt, J=7.8, 1.5 Hz, 1H),7.61-7.55 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.11(s, 9H). LRMS (ESI+) m/z 413.1 (M³⁵Cl+H)⁺, 415.1 (M³⁷Cl+H)⁺; (ESI−) m/z411.1 (M³⁵Cl—H)⁻; HRMS (ESI+) m/z calculated for C₁₇H₂₁ClN₄O₄S (M+H)⁺413.10448, found 413.10573.

2-Chloro-5-ethyl-N⁴-(3-methoxy-4-chlorophenyl)pyrimidin-4-amine(MA1-025) and5-Ethyl-N⁴,N²-bis-[4-chloro-3-methoxyphenyl]pyrimidine-2,4-diamine(MA1-025B)

This was prepared from MA1-012 (0.531 g) and 3-methoxy-4-chloroaniline(0.473 g) using procedure A (reaction time, 16 h) to give the titlecompound as a white solid (0.202 g, 23%). Mp: 143-144° C. ¹H NMR (400MHz, DMSO-d₆): δ 8.93 (s, 1H, disappeared on D₂O shake), 8.07 (s, 1H),7.53 (d, J=2.3 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.31 (dd, J=8.6, 2.3 Hz,1H), 3.83 (s, 3H), 2.61 (q, J=7.4 Hz, 2H), 1.17 (t, J=7.4 Hz, 3H).HPLC-MS (ESI+): m/z 300.1 [70%, (M³⁷Cl³⁵Cl+H)⁺], m/z 298.1 [100%,(M³⁵Cl³⁵Cl+H)⁺]. Further elution gave the bis-addition side productMA1-025B (109 mg, 9%) as a yellow solid, Mp: 201° C. (dec). HPLC: 99%[t_(R)=8.1 min, 65% MeOH, 35% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.20 (s, 1H, disappeared on D₂O shake), 8.48 (s,1H, 40% reduced on D₂O shake), 7.97 (s, 1H), 7.56 (d, J=2.3 Hz, 1H),7.43 (d, J=2.3 Hz, 1H), 7.38 (dd, J=8.6, 2.3 Hz, 1H), 7.32 (d, J=8.7 Hz,1H) 7.29 (dd, J=8.6, 2.3 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 3.74 (s, 3H),3.60 (s, 3H), 2.57 (q, J=7.4 Hz, 2H), 1.18 (t, J=7.4 Hz, 3H). HPLC-MS(ESI+): m/z 421.1 [70%, (M³⁷Cl³⁵Cl+H)⁺], 419.2 [100%, (M³⁵Cl³⁵Cl+H)⁺].LC-MS (ESI+): 421.1 [70%, (M³⁷Cl³⁵Cl+H)⁺], 419.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].HRMS (ESI+): m/z calcd for C₂₀H₂₀Cl₂N₄O₂ (M+H)⁺ 419.1036, found419.1035.

2,5-Dichloro-N⁴-(3,4-dimethoxyphenyl)pyrimidin-4-amine (MA1-059)

This was prepared from 2,4,5-trichloropyrimidine (0.367 g) and3,4-dimethoxyaniline (0.322 g) using procedure B (reaction time, 2 h) togive the title compound as a gray solid (0.540 g, 90%). Mp: 130° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.42 (s, 1H, disappeared on D₂Oshake), 8.33 (s, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.12 (dd, J=8.7, 2.4 Hz,1H), 6.97 (d, J=8.7 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H). HPLC-MS (ESI+):m/z 623.1 [20%, (M³⁵Cl³⁵Cl+M³⁵Cl³⁷Cl+Na)⁺], 302.1 [70%, (M³⁵Cl³⁷Cl+H)⁺],300.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(3-methoxyphenyl)pyrimidin-4-amine (MA1-060)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g) and3-methoxyaniline (0.258 g) using procedure B (reaction time, 72 h) togive the title compound as a white solid (0.342 g, 68%). Mp: 104-106° C.¹H NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H, disappeared on D₂O shake),8.06 (d, J=0.9 Hz, 1H), 7.34-7.32 (m, 1H), 7.28-7.24 (m, 2H), 6.72-6.67(m, 1H), 3.76 (s, 3H), 2.17 (d, J=0.8 Hz, 3H). HPLC-MS (ESI+): m/z 352.2[40%, (M³⁷Cl+H)⁺], 350.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(3-ethoxyphenyl)pyrimidin-4-amine (MA1-061)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g) and3-ethoxyaniline (0.288 g) using procedure B (reaction time, 72 h) togive the title compound as an off white solid (0.332 g, 63%). Mp: 114°C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (s, 1H disappeared on D₂Oshake), 8.05 (d, J=0.8 Hz, 1H), 7.33-7.31 (m, 1H), 7.27-7.21 (m, 2H),6.70-6.64 (m, 1H), 4.02 (q, J=7.0 Hz, 2H), 2.17 (d, J=0.6 Hz, 3H), 1.34(t, J=7.0 Hz, 3H). HPLC-MS (ESI+): m/z 266.2 [40%, (M³⁷Cl+H)⁺], 264.2[100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(3,4-dimethoxyphenyl)pyrimidin-4-amine (MA1-062)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g) and3,4-dimethoxyaniline (0.322 g) using procedure B (reaction time, 72 h)to give the title compound as a beige solid (0.341 g, 61%). Mp: 192° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H, 1H disappeared on D₂Oshake), 7.99 (d, J=0.9 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.17 (dd, J=8.7,2.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 3.75 (s, 3H), 3.745 (s, 3H), 2.14(d, J=0.9 Hz, 3H). HPLC-MS (ESI+): m/z 282.2 [40%, (M³⁷Cl+H)⁺], 380.2[100%, (M³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(3,5-dimethoxyphenyl)pyrimidin-4-amine (MA1-069)

This was prepared from 2,4,5-trichloropyrimidine (0.326 g) and3,5-dimethoxyaniline (0.306 g) using procedure B (reaction time, 10 min)to give the title compound as a white solid (0.512 g, 85%). Mp: 150-151°C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H, disappeared on D₂O shake),8.40 (s, 1H), 6.93 (d, J=2.2 Hz, 2H), 6.34 (t, J=2.2 Hz, 1H), 3.74 (s,6H). HPLC-MS (ESI+): m/z 302.1 [70%, (M³⁷Cl³⁵Cl+H)⁺], 300.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-propyl-N⁴-(3-methoxy-4-chlorophenyl)pyrimidin-4-amine(MA1-072)

This was prepared from MA1-039 (0.262 g) and 3-methoxy-4-chloroaniline(0.227 g) using procedure B (reaction time, 67 h) to give the titlecompound as a white solid (0.116 g, 27%). Mp: 142-142° C. ¹H NMR (400MHz, DMSO-d₆): δ 10.04 (s, 1H, disappeared on D₂O shake), 8.43 (s, 1H),7.66 (s, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 3.82 (s, 3H), 2.54 (t, J=7.5Hz, 2H), 1.58 (sextet, J=7.5 Hz, 2H), 0.92 (t, J=7.5 Hz, 3H). HPLC-MS(ESI+): m/z 314.1 [70%, (M³⁵Cl³⁷Cl+H)⁺], 312.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-iodo-N⁴-(3-methoxy-4-chlorophenyl)pyrimidin-4-amine (MA1-092)

This was prepared from 2,4-dichloro-5-iodopyrimdine (0.550 g) and3-methoxy-4-chloroaniline (0.315 g) using procedure B (reaction time, 1h) to give the title compound as a gray solid (0.708 g, 90%). Mp:190-192° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s, 1H, disappearedon D₂O shake), 8.59 (s, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.41 (d, J=8.6 Hz,1H), 7.21 (dd, J=8.6, 2.3 Hz, 1H), 3.84 (s, 3H). HPLC-MS (ESI+): m/z397.9 [78%, (M³⁵Cl³⁷Cl+H)⁺], 395.9 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(4-chloro-3-ethoxyphenyl)pyrimidin-4-amine (MA2-016-1)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.116 g),4-chloro-3-ethoxyaniline (0.108 g), and DIPEA (0.121 mL) using procedureB (reaction time, 2 h). The product precipitated when the reaction wascooled to room temperature. The reaction mixture was vigorously shakenafter water (5 mL) was added. Finally the product was filtered using asintered funnel and rinsed with water (3×10 mL) and hexane (3×10 mL).The title compound was obtained as a white solid (0.156 g, 78%). Mp:102-104° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.57 (s, 1H, disappeared on D₂Oshake), 8.42 (s), 7.48 (d, J=2.3 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.26(dd, J=8.6, 2.3 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).HPLC-MS (ESI+): m/z 342.0 [20%, (M³⁵Cl³⁷Cl+Na)⁺], 320.0 [70%,(M³⁵Cl³⁷Cl+H)⁺], 318.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(4-chloro-3-ethoxyphenyl)pyrimidin-4-amine(MA2-016-2)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.103 g),4-chloro-3-ethoxyaniline (0.108 g), and DIPEA (0.121 mL) using procedureB (reaction time, 3 days). The product precipitated when the reactioncooled to room temperature. The title compound MA2-016-2 was obtained,in same way as that used to isolate MA2-016-1 as a gray-white solid(0.154 g, 82%). Mp: 180° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 8.90 (s,1H, disappeared on D₂O shake), 8.09 (s, 1H), 7.55 (d, J=2.1 Hz, 1H),7.39 (d, J=8.6 Hz, 1H), 7.30 (dd, J=8.6, 2.1 Hz, 1H), 4.11 (q, J=6.9 Hz,2H), 2.18 (s, 3H), 1.39 (t, J=6.9 Hz, 3H). HPLC-MS (ESI+): m/z 300.1[70%, (M³⁵Cl³⁷Cl+H)⁺], 298.2 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(4-chloro-3-ethoxyphenyl)quinazoline-4-amine (MA2-030)

This was prepared from MA2-028 (0.398 g), 4-chloro-3-ethoxyaniline(0.315 g), and DIPEA (0.418 mL) using procedure B (reaction time, 18 h).Water (6 mL) was added and the precipitated product was filtered, washedwith water (3×10 mL), hexanes (3×10 mL), and dried to give the titlecompound MA2-030 as a gray solid (0.633 g, 99%). Mp: 265° C. (dec). ¹HNMR (400 MHz, DMSO-d₆): δ 10.25 (s, 1H, disappeared on D₂O shake), 8.58(d, J=7.7 Hz, 1H), 7.91 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.77-7.74 (m,2H), 7.68 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.51-7.45 (m, 2H), 3.89 (s,3H). HPLC-MS (ESI+): m/z 322.1 [70%, (M³⁵Cl³⁷Cl+H)⁺], 320.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-([3-(N-1,1-dimethylethyl)sulfamoyl]phenyl)quinazoline-4-amine(MA2-033)

This was prepared from MA2-028 (0.070 g), SG1-137 (0.080 g), and DIPEA(0.067 mL) using procedure B (reaction time, 2 h) and isolated in thesame way as MA2-030 give the title compound MA2-033 as a gray solid(0.104 g, 76%). Mp: 286° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 10.43(s, 1H, disappeared on D₂O shake), 8.60 (d, J=8.3 Hz, 1H), 8.28 (s, 1H),8.06 (ddd, J=9.2, 4.8, 3.1 Hz, 1H), 7.96-7.88 (m, 1H), 7.75 (d, J=8.4Hz, 1H), 7.72-7.66 (m, 1H), 7.65-7.62 (m, 2H), 7.60 (s, 1H, disappearedon D₂O shake), 1.15 (s, 9H). HPLC-MS (ESI+): m/z 393.1 [40%,(M³⁵Cl³⁷Cl+H)⁻], 391.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3-(methanesulfonamido)phenyl]pyrimidin-4-amine(MA2-035)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g),N-(3-aminophenyl)methanesulfonamide (0.372 g) and DIPEA (0.418 mL) usingprocedure B (reaction time, 48 h) and isolated in the same way asMA2-030 to give the title compound MA2-035 as a gray solid (0.374 g,100%). Mp: 191-193° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.85 (s, 1H,disappeared on D₂O shake), 8.95 (s, 1H, disappeared on D₂O shake), 8.06(d, J=0.9 Hz, 1H), 7.54 (t, J=1.9 Hz, 1H), 7.35 (dd, J=8.4, 1.5 Hz, 1H),7.30 (t, J=8.0 Hz, 1H), 6.91 (ddd, J=7.8, 2.0, 1.1 Hz, 1H), 3.05 (s,3H), 2.17 (s, 3H). HPLC-MS (ESI+): m/z 315.2 [40%, (M³⁵Cl³⁷Cl+H)⁺],313.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-[3-(cyclopropanesulfonamido)phenyl]quinazoline-4-amine(MA2-038)

This was prepared from MA2-028 (0.199 g), RJ-025 (0.212 g), and DIPEA(0.1 mL) using procedure B (reaction time, 16 h) and isolated in thesame way as MA2-030 to give the title compound MA2-038 as a gray solid(0.374 g, 100%). Mp: 198-203° C. ¹H NMR (400 MHz, DMSO-d₆): δ ¹H NMR(400 MHz, dmso) δ 10.25 (s, 1H, disappeared on D₂O shake), 9.87 (s, 1Hdisappeared on D₂O shake), 8.57 (d, J=8.3 Hz, 1H), 7.93-7.84 (m, 1H),7.73-7.70 (m, 2H), 7.68-7.62 (m, 1H), 7.53 (dd, J=8.1, 1.0 Hz, 1H), 7.35(t, J=8.1 Hz, 1H), 7.06-6.99 (m, 1H), 2.73-2.66 (m, 1H), 1.03-0.92 (m,4H). HPLC-MS (ESI+): m/z 377.1 [40%, (M³⁵Cl³⁷Cl+H)⁺], 375.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3-(2,2-dimethylpropanamido)phenyl]pyrimidin-4-amine(MA2-042-1)

This was prepared from MA2-040-1 (0.192 g),2,4-dichloro-5-methylpyrimidine (0.163 g), and DIPEA (0.192 mL) usingprocedure B (reaction time, 48 h) and isolated in the same way asMA2-030 give the title compound MA2-042-1 as a gray solid (0.241 g,76%). Mp: 178° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H, 10%reduced on D₂O shake), 8.86 (s, 1H, 80% reduced on D₂O shake), 8.02 (s,1H), 7.85 (brs, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H),7.25 (t, J=7.8 Hz, 1H), 2.14 (s, 3H), 1.21 (s, 9H). HPLC-MS (ESI+): m/z321.2 [40%, (M³⁵Cl³⁷Cl+H)⁺], 319.2 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3-(2-methylpropanamido)phenyl]pyrimidin-4-amine(MA2-042-2)

This was prepared from MA2-040-2 (0.178 g),2,4-dichloro-5-methylpyrimidine (0.163 g), and DIPEA (0.192 mL) usingprocedure B (reaction time, 48 h) and isolated in the same way asMA2-030 to give the title compound MA2-042-2 as a gray solid (0.233 g,77%). Mp: 186-189° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H, 50%reduced on D₂O shake), 8.88 (s, 1H, disappeared on D₂O shake), 8.03 (s,1H), 7.87 (s, 1H), 7.38-7.23 (m, 3H), 2.60 (septet, J=6.8 Hz, 1H), 2.16(s, 3H), 1.10 (d, J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z 307.1 [40%,(M³⁵Cl³⁷Cl+H)⁺], 305.2 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3-(cyclopropanecarboxamido)phenyl]pyrimidin-4-amine(MA2-042-3)

This was prepared from MA2-040-3 (0.176 g),2,4-dichloro-5-methylpyrimidine (0.163 g), and DIPEA (0.192 mL) usingprocedure B (reaction time, 48 h) and isolated in the same way asMA2-030 to give the title compound MA2-042-2 to give the title compoundMA2-042-3 as a gray solid (0.219 g, 72%). Mp: 230-232° C. ¹H NMR (400MHz, DMSO-d₆): δ 10.22 (s, 1H, 40% reduced on D₂O shake), 8.87 (s, 1H,disappeared on D₂O shake), 8.03 (d, J=0.7 Hz, 1H), 7.85 (s, 1H),7.35-7.24 (m, 3H), 2.15 (s, 3H), 1.80 (quintet, J=6.2 Hz, 1H), 0.79 (d,J=6.2 Hz, 4H). HPLC-MS (ESI+): m/z 305.1 [40%, (M³⁵Cl³⁷Cl+H)⁺], 303.2[100%, (M³⁵Cl³⁵Cl+H)].

2-Chloro-5-bromo-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-pyrimidin-4-amine(MA1-001)

This was prepared from 2-chloro-5-bromopyrimidine (0.401 g) and SG1-147(0.434 g) using procedure A (reaction time, 16 h) to give the titlecompound as a white solid (0.482 g, 68%). Mp: 212° C. (dec). ¹H NMR (400MHz, DMSO-d₆): 9.59 (s, 1H, disappeared on D₂O shake), 8.52 (s, 1H),8.06-8.03 (m, 1H), 7.83-7.78 (m, 1H), 7.63-7.58 (m, 3H, 1H disappearedon D₂O shake), 3.30 (octet, J=6.5 Hz, 1H), 0.97 (d, J=6.5 Hz, 6H).HPLC-MS (ESI+): m/z 409.0 [40%, (M⁸¹Br³⁷Cl+H)⁺], 407.0 [100%,(M⁷⁹Br³⁷Cl+H and M¹Br³⁵C₁)⁺], 405.1 [100%, (M⁷⁹Br³⁵Cl+H)⁺].

2-Chloro-5-ethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)pyrimidin-4-amine(MA1-017)

This was prepared from MA1-012 (0.354 g) and SG1-137 (0.457 g) usingprocedure A (reaction time, 16 h) to give the title compound as a whitesolid (0.318 g, 43%). Mp: 209-210° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.16(s, 1H, disappeared on D₂O shake), 8.14-8.07 (m, 2H), 7.90-7.81 (m, 1H),7.59-7.52 (m, 3H, 1H disappeared on D₂O shake), 2.64 (q, J=7.4 Hz, 2H),1.19 (t, J=7.4 Hz, 3H), 1.13 (s, 9H). HPLC-MS (ESI+): m/z 371.2 [40%,(M³⁷Cl+H)], 369.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methylethyl-N-[3-methoxy-4-chlorophenyl]-pyrimidin-4-amine(MA1-073)

This was prepared from MA1-039 (0.262 g) and 3-methoxy-4-chloroaniline(0.227 g) using procedure B (reaction time, 36 h) and isolated in thesame way as MA2-030 to give the title compound MA1-073 as a white solid(0.097 g, 31%). Mp: 230° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 10.05(s, 1H, 70% on D₂O shake), 8.50 (s, 1H), 7.69 (s, 1H), 7.31 (d, J=8.4Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 3.82 (s, 3H), 3.08 (dt, J=13.8, 6.9 Hz,1H), 1.24 (d, J=6.9 Hz, 6H). HPLC-MS (ESI+): m/z 314.1 [20%,(M³⁵Cl³⁷Cl+H)⁺], 312.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(3-[3-(methylethyl)ureido]phenyl)-pyrimidin-4-amine(MA2-058-2)

This was prepared from MA2-056-2 (0.193 g) and2,4-dichloro-5-methylpyrimidine (0.163 g) using procedure B (reactiontime, 48 h) and isolated in the same way as MA2-030 to give the titlecompound MA2-058-2 as a white solid (0.263 g, 82%). Mp: 248° C. (dec).¹H NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H, 80% reduced on D₂O shake),8.30 (s, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.62 (s, 1H), 7.23-7.11 (m, 3H),6.02 (d, J=7.5 Hz, 1H, 20% reduced on D₂O shake), 3.77-3.71 (m, 1H),2.15 (s, 3H), 1.09 (d, J=6.5 Hz, 6H). HPLC-MS (ESI+): m/z 322.2 [40%,(M³⁷Cl+H)⁺], 320.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine(MA2-098-1)

This was prepared from MA2-092 (0.189 g) and SG1-137 (0.228 g) usingprocedure B (reaction time, 3 days) and isolated in the same way asMA2-030 to give the title compound MA2-098-1 as a white solid (0.197 g,52%). Mp: 230° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H,disappeared on D₂O shake), 8.13 (brd, J=1.8 Hz, 1H), 7.94 (dt, J=7.5,1.8 Hz, 1H), 7.58-7.48 (m, 3H, 1H disappeared on D₂O shake), 2.83 (t,J=7.6 Hz, 4H), 2.08 (quintet, J=7.6 Hz, 2H), 1.13 (s, 9H). HPLC-MS(ESI+): m/z 383.2 [40%, (M³⁷Cl+H)⁺], 381.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine(MA2-098-2)

This was prepared from MA2-092 (0.189 g) and SG1-147 (0.214 g) usingprocedure B (reaction time, 3 days) and isolated in the same way asMA2-030 to give the title compound MA2-098-2 as a white solid (0.220 g,60%). Mp: 212° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.41 (s, 1H,disappeared on D₂O shake), 8.13 (t, J=1.9 Hz, 1H), 8.01-7.98 (m, 1H),7.57 (t, J=8.1 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 3.3-3.26 (m, 1H,partially overlapped by residual DMSO solvent signal), 2.83 (t, J=7.7Hz, 4H), 2.08 (quintet, J=7.7 Hz, 2H), 0.97 (d, J=6.5 Hz, 6H). HPLC-MS(ESI+): m/z 369.2 [40%, (M³⁷Cl+H)⁺], 367.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-(N-cyclopropylsulfamoyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine(MA2-098-3)

This was prepared from MA2-092 (0.189 g) and RJ1-025 (0.212 g) usingprocedure B (reaction time, 3 days) and isolated in the same way asMA2-030 to give the title compound MA2-098-3 as a white solid (0.198 g,54%). Mp: 216° C. (dec). H NMR (400 MHz, DMSO-d₆): δ 9.44 (s, 1H,disappeared on D₂O shake), 8.15 (t, J=1.9 Hz, 1H), 8.01 (dd, J=8.0, 1.3Hz, 1H), 7.95 (d, J=2.4 Hz, 1H, disappeared on D₂O shake), 7.59 (t,J=8.0 Hz, 1H), 7.49 (8.01 (dd, J=8.0, 1.3 Hz, 1H)), 2.83 (t, J=7.6 Hz,4H), 2.2-2.14 (m, 1H), 2.08 (quintet, J=7.8 Hz, 2H), 0.56-0.48 (m, 2H),0.47-0.38 (m, 2H). HPLC-MS (ESI+): m/z 367.1 [40%, (M³⁷Cl+H)⁺], 365.1[100%, (M³⁵Cl+H)].

5-Bromo-N⁴-[4-chloro-3-methoxyphenyl]-N²-(4-[4-(1,1-dimethylethoxy)carbonylpiperazin-1-yl]phenyl)pyrimidine-2,4-diamine(MA2-010)

This was obtained by stirring MA2-004 (0.698 g) and4-(4-tert-butoxycarbonylpiperazino)aniline (0.555 g) in isopropanol (4mL) at 85° C. (oil bath) for 24 h. The reaction mixture was allowed tocool to room temperature and diluted with water (50 mL) which led to theprecipitation of product. The crude product was filtered and washed withwater (4×10 mL) and hexane (4×10 mL) to provide MA2-010 as a grey solid(0.960 g, 81%). Mp: 194-195° C. ¹H NMR (400 MHz, DMSO-d₆ acquired at 70°C.): δ 8.92 (s, 1H, disappeared on D₂O shake), 8.41 (s, 1H, disappearedon D₂O shake), 8.17 (s, 1H), 7.43-7.37 (m, 3H), 7.34-7.28 (m, 2H), 6.82(d, J=9.0 Hz, 2H), 3.75 (s, 3H), 3.50-3.45 (m, 4H), 3.06-3.00 (m, 4H),1.44 (s, 9H). HPLC-MS (ESI+): m/z 591.2 [100%, (M⁸¹Br³⁵Cl+H)⁺ and(M⁷⁹Br³⁷Cl+H)⁺], 589.2 [70%, (M⁷⁹B³⁵Cl+H)⁺].

2-Chloro-5-fluoro-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-pyrimidin-4-amine(MA3-061)

This was prepared from 2-chloro-5-fluoro-pyrimidine (0.084 g) andMA3-010 (0.114 g) using procedure B (reaction time, 3 days) and isolatedin the same way as MA2-030 to give the title compound MA3-061 as a whitesolid (0.147 g, 81%). Mp: 194-196° C. ¹H NMR (400 MHz, DMSO-ds): δ 10.05(s, 1H, disappeared on D₂O shake), 9.73 (s, 1H, disappeared on D₂Oshake), 8.33 (d, J=3.4 Hz, 1H), 7.71 (s, 1H), 7.37 (d, J=8.0 Hz, 1H),7.27 (t, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 1.30 (s, 9H). HPLC-MS(ESI+): m/z 361.1 [40%, (M³⁷Cl+H)⁺], 359.1 [100%, (M³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(3-ethoxyphenyl)pyrimidin-4-amine (MA1-058)

This was prepared from 2,4,5-trichloropyrimidine (0.367 g) and3-ethoxyaniline (0.288 g) using procedure B (reaction time, 2 h) andisolated in the same way as MA2-030 to give the title compound MA1-058as a white solid (0.168 g, 91%). Mp: 89-91° C. ¹H NMR (400 MHz,DMSO-d₆): δ 9.46 (s, 1H, disappeared on D₂O shake), 8.39 (s, 1H), 7.27(t, J=8.2 Hz, 1H), 7.24 (t, J=2.1 Hz, 1H), 7.17 (d, with unresolved finecoupling, J=8.2 Hz, 1H), 6.74 (ddd, J=8.2, 2.4, 0.8 Hz, 1H), 4.02 (q,J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H). HPLC-MS (ESI+): m/z 286.1 [70%,(M³⁵Cl³⁷Cl+H)⁺], 284.1 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine(MA3-002-2)

This was prepared from MA2-096 (0.096 g) and SG1-147 (0.107 g) usingprocedure B (reaction time, 18 h, reaction temperature 100° C.) andisolated in the same way as MA2-030 to give the title compound MA3-002-2as a white solid (0.168 g, 91%). Mp: 268° C. ¹H NMR (400 MHz, DMSO-d₆):δ 9.81 (s, 1H, disappeared on D₂O shake), 8.07 (t, J=1.8 Hz, 1H), 7.95(ddd, J=8.1, 1.8, 1.0 Hz, 1H), 7.60 (d, J=7.2 Hz, disappeared on D₂Oshake, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.50 (ddd, J=8.1, 1.8, 1.1 Hz, 1H),4.99 (t, J=2.5 Hz, 2H), 4.85 (t, J=2.5 Hz, 2H), 3.28 (quint, J=6.5 Hz,1H), 0.95 (d, J=6.5 Hz, 6H). HPLC-MS (ESI+): m/z 371.1 [40%,(M³⁷Cl+H)⁺], 369.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[N-cyclopropylsulfamoyl]phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine(MA3-002-3)

This was prepared from MA2-096 (0.096 g) and RJ1-042 (0.212 g) usingprocedure B (reaction time, 18 h, reaction temperature 100° C.) andisolated in the same way as MA2-030 to give the title compound MA3-002-3as a white solid (0.165 g, 90%). Mp: 208° C. (dec). ¹H NMR (400 MHz,DMSO-d₆): δ 9.86 (s, 1H, disappeared on D₂O shake), 8.10 (s, 1H), 8.00(d with unresolved fine coupling, J=8.2, Hz, 1H), 7.96 (d, J=2.3 Hz, 1H,disappeared on D₂O shake), 7.62 (t, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz,1H), 5.02 (s, 2H), 4.87 (s, 2H), 2.22-2.12 (m, 1H), 0.56-0.48 (m, 2H),0.47-0.38 (m, 2H). HPLC-MS (ESI+): m/z 757.1 [20%, (2M³⁷Cl+Na)⁺], 755.1[30%, (2M³⁵Cl+Na)⁺], 369.1 [40%, (M³⁷Cl+H)⁺], 367.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine(MA3-014-1)

This was prepared from MA2-092 (0.095 g) and MA3-010 (0.114 g) usingprocedure B (reaction time, 3 days) and isolated in the same way asMA2-030 to give the title compound MA3-014-1 as a white solid (0.110 g,52%). Mp: 217° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H, 80%reduced on D₂O shake), 9.14 (s, 1H, 85% reduced on D₂O shake), 7.59 (s,1H), 7.34 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz,1H), 2.78 (t, J=7.7 Hz, 4H), 2.04 (quint, J=7.7 Hz, 2H), 1.28 (s, 9H).HPLC-MS (ESI+): m/z 383.2 [40%, (M³⁷Cl+H)⁺], 381.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine(MA3-016-1)

This was prepared from MA2-096 (0.096 g) and MA3-010 (0.114 g) usingprocedure B (reaction time, 2 days) and isolated in the same way asMA2-030 to give the title compound MA3-016-1 as a white solid (0.138 g,69%). Mp: 194° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H,disappeared on D₂O shake), 9.60 (s, 1H, disappeared on D₂O shake), 7.57(s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 4.96 (s, 2H), 4.84 (s, 2H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z385.2 [40%, (M³⁷Cl+H)⁺], 383.2 [100%, (M³⁵Cl+H)].

2-Chloro-N⁴-[3-(cyclopropylsulfonamido)phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine(MA3-016-3)

This was prepared from MA2-096 (0.096 g) and RJ1-025 (0.106 g) usingprocedure B (reaction time, 2 days) and isolated in the same way asMA2-030 to give the title compound MA3-016-3 as a white solid (0.129 g,70%). Mp: 237° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.86 (s, 1H,disappeared on D₂O shake), 8.10 (t, J=1.9 Hz, 1H), 8.00 (ddd, J=8.1,2.1, 0.9 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H, disappeared on D₂O shake), 7.63(t, J=8.1 Hz, 1H), 7.53 (ddd, J=8.1, 2.1, 0.9 Hz, 1H), 5.02 (t, J=2.5Hz, 2H), 4.87 (t, J=2.5 Hz, 2H), 2.21-2.15 (m, 1H), 0.55-0.47 (m, 2H),0.47-0.39 (m, 2H). HPLC-MS (ESI+): m/z 369.1 [40%, (M³⁷Cl+H)⁺], 367.1[100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-5,6,7,8-tetrahydroquinazoline-4-amine(MA3-064-1)

This was prepared from MA2-10 (0.114 g) and MA3-034 (0.102 g) usingprocedure B (reaction time, 4 days). The volatiles were evaporated underthe reduced pressure and the product was purified via columnchromatography (SiO₂) eluting with hexanes/EtOAc (1:9 to 1:2 v/v) togive the title compound MA3-064-1 as a gray solid (0.087 g, 44%). Mp:265° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H, disappeared onD₂O shake), 8.73 (s, 1H, disappeared on D₂O shake), 7.56 (s, 1H),7.26-7.22 (m, 2H), 7.02-6.98 (m, 1H), 2.62 (t, J=6.1 Hz, 2H), 2.47-2.43(m, 2H, partially overlapped by residual DMSO solvent signal), 1.81-1.73(m, 4H), 1.30 (s, 9H). ¹H NMR (400 MHz, CD₃OD) δ 7.73-7.70 (m, 1H),7.27-7.24 (m, 2H), 7.11-7.05 (m, 1H), 4.63 (s, 1H), 2.69 (t, J=6.0 Hz,3H), 2.55 (t, J=6.0 Hz, 2H), 1.92-1.86 (m, 4H), 1.39 (s, 19H). HPLC-MS(ESI+): m/z 397.2 [40%, (M³⁷Cl+H)⁺], 395.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-fluoro-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)pyrimidine-4-amine(MA3-070)

This was prepared from SG3-010 (0.043 g) and2,4-dichloro-5-fluoropyrimidine (0.027 g) using procedure B (reactiontime, 4 h) and isolated in the same way as MA2-030 to give the titlecompound MA3-070 as a white solid (0.054 g, 86%). Mp: 223° C. (dec). ¹⁹FNMR (376 MHz, DMSO-d₆): δ −152.98 (s). ¹H NMR (400 MHz, DMSO-d₆): δ10.17 (s, 1H, disappeared on D₂O shake), 9.34 (s, 1H, disappeared on D₂Oshake), 8.36 (d, J=3.4 Hz, 1H), 8.03 (d, J=2.6 Hz, 1H), 7.63 (dd, J=8.8,2.6 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 1.34 (s, 9H). HPLC-MS (ESI+): m/z807.1 [30%, (2M³⁵Cl³⁵Cl+Na)⁺], 395.1 [70%, (M³⁵Cl³⁷C+H)⁺], 393.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-([3-phenylsulfonamido]phenyl)pyrimidine-4-amine(MA4-006-1)

This was prepared from MA3-092 (0.124 g) and2,4-dichloro-5-methylpyrimidine (0.082 g) using procedure B (reactiontime, 2.5 days) and isolated in the same way as MA2-030 to give thetitle compound MA4-006-1 as a beige solid (0.128 g, 69%). Mp: 199° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 10.36 (s, 1H, disappeared on D₂Oshake), 8.85 (s, 1H), 8.05 (d, J=0.9 Hz, 1H), 7.85-7.80 (m, 2H),7.63-7.58 (t, J=7.4 Hz with fine coupling, 1H), 7.57-7.52 (m, 3H), 7.30(ddd, J=8.0, 2.0, 0.9 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.81 (ddd, J=8.0,2.0, 0.9 Hz, 1H), 2.14 (d, J=0.7 Hz, 3H). HPLC-MS (ESI+): m/z 777.2[10%, (2M³⁵Cl+Na)⁺], 377.1 [40%, (M³⁷Cl+H)⁺], 375.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[(1-methylethyl)sulfonamido]phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine(MA3-016-2)

This was prepared from MA2-096 (0.096 g) and MA3-004 (0.107 g) usingprocedure B (reaction time, 2 days) and isolated in the same way asMA2-030 to give the title compound MA3-016-2 as a white solid (0.121 g,66%). Mp: 241° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): 9.88 (s, 1H,disappeared on D₂O shake), 9.62 (s, 1H, disappeared on D₂O shake), 7.54(s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.0Hz, 1H), 4.97 (s, 2H), 4.84 (s, 2H), 3.33-3.24 (m, 1H, appeared from theoverlapping water signal on D₂O shake) 1.26 (d, J=6.7 Hz, 6H). HPLC-MS(ESI+): m/z 761.2 [13%, (M³⁵Cl+M³⁷Cl+Na)⁺], 759.2 [12%, (2M³⁵Cl+Na)⁺],371.1 [40%, (M³⁷Cl+H)⁻], 369.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(4-methyl-[3-(N-cyclobutyl)sulfamoyl]phenyl)-pyrimidine-4-amine(MA4-082)

This was prepared from MA4-080 (0.736 g) and2,4-dichloro-5-methylpyrimidine (0.499 g) using procedure B (reactiontime, 3.5 days) and isolated in the same way as MA2-030 to give thetitle compound MA4-082 as a yellow solid (0.558 g, 50%). Mp: 237° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.09 (s, 1H, disappeared on D₂Oshake), 8.10 (d, J=2.1 Hz, 1H), 8.08 (t, J=0.9 Hz, 1H), 7.97 (d, J=8.3Hz, 1H, disappeared on D₂O shake), 7.78 (dd, J=8.2, 2.2 Hz, 1H), 7.36(d, J=8.2 Hz, 1H), 3.62-3.56 (m, 1H), 2.56 (s, 3H), 2.17 (s, 3H),1.93-1.87 (m, 2H), 1.84-1.73 (m, 2H), 1.55-1.37 (m, 2H). HPLC-MS (ESI+):m/z 369.1 [40%, (M³⁷Cl+H)⁺], 367.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(3-[(1-methylcyclopropyl)sulfonamido]phenyl)-pyrimidine-4-amine(MA4-98)

This was prepared from MA4-096 (0.450 g) and2,4-dichloro-5-methylpyrimidine (0.324 g) using procedure B (reactiontime, 2.5 days). The reaction mixture was diluted with ethyl acetate (40mL) and washed with water (50 mL). The product was purified via columnchromatography (SiO₂) eluting with hexanes/EtOAc (1:9 to 1:4 v/v) togive the title compound MA4-098 as a yellow solid (0.279 g, 45%). Mp:215° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.83 (s, 1H, disappeared onD₂O shake), 8.91 (s, 1H, 50% reduced on D₂O shake), 8.05 (d, J=0.9 Hz,1H), 7.59 (t, J=2.0 Hz, 1H), 7.341 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.27(t, J=8.0 Hz, 1H), 6.98 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 2.17 (d, J=0.7Hz, 3H), 1.43 (s, 3H), 1.20-1.14 (m, 2H), 0.77-0.71 (m, 2H). HPLC-MS(ESI+): m/z 355.1 [40%, (M³⁷Cl+H)⁺], 353.1 [100%, (M³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-(3-methoxyphenyl)pyrimidine-4-amine (MA1-055-1)

This was prepared from m-anisidine (0.246 g) and2,4,5-trichloropyrimidine (0.367 g) using procedure B (reaction time, 1h) and isolated in the same way as MA2-030 to give the title compoundMA1-055-1 as a white solid (0.476 g, 88%). Mp: 100-101° C. ¹H NMR (400MHz, DMSO-d₆): δ 9.45 (s, 1H, disappeared on D₂O shake), 8.38 (s), 7.28(t, J=8.1 Hz, 1H), 7.24 (t, J=2.1 Hz, 1H), 7.20 (d, with unresolved finecoupling, J=8.1 Hz, 1H), 6.75 (d, with unresolved fine coupling, J=8.1Hz, 1H), 3.74 (s, 3H). HPLC-MS (ESI+): m/z 272.1 [70%, (M³⁵Cl³⁷Cl+H)⁺],270.2 [100%, (M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(4-fluoro-3-[(1,1-dimethylethyl)sulfonamido]phenyl)-pyrimidine-4-amine(MA4-025)

This was prepared from MA4-024 (0.2123 g) and2,4-dichloro-5-methylpyrimidine (0.3082 g) using procedure B (reactiontime, 2.5 days) and isolated in the same way as MA2-030 to give thetitle compound MA4-025 as a yellow solid (0.095 g, 51%). Mp: 268° C.(dec). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −127.93 (s). ¹H NMR (400 MHz,DMSO-d₆): δ 9.54 (s, 1H, 90% reduced on D₂O shake), 8.94 (s, 1H, 85%reduced on D₂O shake), 8.05 (d, J=0.9 Hz, 1H), 7.78 (dd, J=7.3, 2.7 Hz,1H), 7.47 (ddd, J=9.0, 4.2, 2.7 Hz, 1H), 7.25 (dd, J=10.1, 9.0 Hz, 1H),2.16 (d, J=0.7 Hz, 3H), 1.32 (s, 9H). HPLC-MS (ESI+): m/z 769.2 [10%,(M³⁷Cl+M³⁵Cl+Na)⁺], 767.2 [10%, (2M³⁵Cl+Na)⁺], 375.1 [40%, (M³⁷Cl+H)⁺],373.2 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(4-chloro-[3-phenylsulfonamido]phenyl)pyrimidine-4-amine(MA4-006-2)

This was prepared from MA4-002 (0.141 g) and2,4-dichloro-5-methylpyrimidine (0.082 g) using procedure B (reactiontime, 2.5 days) and isolated in the same way as MA2-030 to give thetitle compound MA4-006-2 as a white solid (0.094 g, 46%). Mp: 214° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 8.84 (s, 1H, disappeared on D₂Oshake), 8.02 (d, J=0.7 Hz, 1H, disappeared on D₂O shake), 7.83-7.80 (m,2H, 1H disappeared on D₂O shake), 7.59 (t, with unresolved finecoupling, J=7.3 Hz, 1H), 7.55-7.50 (m, with unresolved fine coupling,3H), 7.23 (d, J=8.9 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.78 (d, withunresolved fine coupling, J=8.0 Hz, 1H), 2.12 (s, 3H). HPLC-MS (ESI+):m/z 841.0 [10%, (2M³⁷Cl³⁵C+Na)⁺], 411.1 [70%, (M³⁵C₁₃₇Cl+H)⁺], 409.1[100%, (M³⁵Cl³⁵Cl+H)⁺].

5-Methyl-N⁴-[3-nitrophenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-104)

This was obtained as a yellow solid (1.3 g, 82%) from MA4-092 (1.00 g)and 4-(4-methylpiperazino)aniline (0.723 g) using the general method x.The product was purified by column chromatography (SiO₂, eluting withDCM-MeOH, 0-12%). Mp: 194-198° C. HPLC: 99% [t_(R)=7.2 min, 35% MeOH,65% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.84(s, 1H, disappeared on D₂O shake), 8.71 (s, 1H, disappeared on D₂Oshake), 8.49 (t, J=2.2 Hz, 1H), 8.36 (d, J=8.1 Hz, 1H), 7.93 (d, J=0.8Hz, 1H), 7.86 (ddd, J=8.1, 2.3, 0.9 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H),7.44 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz, 2H), 3.06-2.97 (m, 4H),2.48-2.39 (m, 4H), 2.21 (s, 3H), 2.12 (d, J=0.8 Hz, 3H). HPLC-MS (ESI+):m/z 420.3 [20%, (M+H)⁺], 210.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): m/z 420.2[100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₂H₂₅N₇O₂ (M+H)⁺ 420.2143,found 420.2146.

2-Chloro-5-methyl-N⁴-[3-(1,1-dimethylethyl)sulfonamidophenyl]pyrimidine-4-amine(MA2-008)

To a solution of MA2-006 (0.140 g) in DCM (10 mL) was added m-CPBA (65%,0.093 g) under Argon. After stirring overnight at room temperature, thereaction mixture was diluted with DCM (50 mL) and washed with saturatedNaHCO₃ (2×25 mL). The organic layer was dried over Na₂SO₄, concentratedand purified via column chromatography (SiO₂) eluting with hexanes/EtOAc(0:10 to 2:8 v/v) to give the title compound MA2-008 as a white solid(0.065 g, 44%). Mp: 254° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.68 (s,1H, 60% reduced on D₂O shake), 8.90 (s, 1H, 10% reduced on D₂O shake),8.05 (d, J=0.9 Hz, 1H), 7.60 (t, J=1.9 Hz, 1H), 7.29 (dt, J=8.0, 1.5 Hz,1H), 7.24 (t, J=8.0 Hz, 1H), 7.02 (ddd, J=8.0, 2.0, 1.5 Hz, 1H), 2.16(d, J=0.9 Hz, 3H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z 357.1 [40%,(M³⁷Cl+H)⁺], 355.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(3-[(1-methylethyl)sulfonamido]phenyl)pyrimidine-4-amine(MA4-008)

This was prepared from MA3-004 (0.107 g) and2,4-dichloro-5-methylpyrimidine (0.082 g) using procedure B (reactiontime, 2.5 days) and isolated in the same way as MA2-030 to give thetitle compound MA4-008 as a white solid (0.088 g, 52%). Mp: 207° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.85 (s, 1H, 85% reduced on D₂Oshake), 8.94 (s, 1H, 30% reduced on D₂O shake), 8.06 (d, J=0.9 Hz, 1H),7.57 (s, 1H), 7.31-7.26 (m, 2H), 6.98-6.90 (m, 1H), 3.33-3.26 (m, 1Hpartially overlapped by residual water signal), 2.16 (s, 3H), 1.27 (d,J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z 343.1 [40%, (M³⁷Cl+H)⁺], 341.2 [100%,(M³⁵Cl+H)⁺].

2,5-Dichloro-N-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-pyrimidine-4-amine(MA4-142)

This was prepared from SG3-105 (0.263 g) and 2,4,5-trichloropyrimidine(0.183 g) using procedure B (reaction time, 4 h) and isolated in thesame way as MA2-030 to give the title compound MA4-025 as a white solid(0.332 g, 81%). Mp: 229-231° C. ¹H NMR (400 MHz, DMSO-d₆): 9.68 (s, 1H,disappeared on D₂O shake), 9.38 (s, 1H, disappeared on D₂O shake), 8.42(s, 1H), 7.91 (s, 1H), 7.51-7.48 (m, 2H), 1.33 (s, 9H). HPLC-MS (ESI+):m/z 841.1 [50%, (M³⁷C₁₃ ⁵C₃ ⁵Cl+2H)⁺²], 411.1 [100%,(M³⁷Cl³⁵Cl³⁵Cl+H)⁺], 409.0 [97%, (M³⁵C₃Cl³⁵Cl+H)⁺].

5-Methyl-N⁴-[3-aminophenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-106)

In a 3-neck round bottom flask, palladium (10% on carbon)(0.248 g,0.0.05 eq.) was added to deoxygenated EtOH (20 mL) under Argon. Theflask was evacuated and back filled with Argon (twice). Argon gas wasevacuated and a balloon of hydrogen was attached to the system. Finally,MA4-104 (1.24 g) was dissolved in DCM (5 mL) and added via a syringe.The reaction mixture was stirred at room temperature for 24 h, filteredusing a short plug of celite and concentrated in vacuo. The filtrate wasconcentrated under reduced pressure to provide the title compoundMA4-106 as a gray solid (1.10 g, 96%). Mp: 180° C. (dec). ¹H NMR (400MHz, CDCl₃) δ: 8.60 (s, 1H, disappeared on D₂O shake), 7.92 (s, 1H,disappeared on D₂O shake), 7.78 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 6.97(brs, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.79 (d,J=9.0 Hz, 2H), 6.29 (d, J=8.0 Hz, 1H), 4.93 (s, 2H, disappeared on D₂Oshake), 3.04-2.98 (m, 4H), 2.46-2.41 (m, 4H), 2.21 (s, 3H), 2.05 (s,3H). HPLC-MS (ESI+): m/z 390.3 [20%, (M+H)⁺], 195.8 [100%, (M+2H)²⁺].

2-Chloro-5-methyl-N⁴-[3-nitrophenyl]pyrimidine-4-amine (MA4-092)

This was prepared from 2,4-dichloro-5-methylpyrimidine (3.26 g) andm-nitroaniline (2.76 g) using procedure B (reaction time 6 days,reaction temperature 155° C.) and isolated in the same way as MA2-030 togive the title compound MA4-092 as a yellow solid (2.46 g, 62%). Mp:172° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.25 (s, 1H, disappeared onD₂O shake), 8.67 (t, J=2.2 Hz, 1H), 8.19 (ddd, J=8.3, 2.2, 0.9 Hz, 1H),8.17 (d, J=0.9 Hz, 1H), 7.95 (ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.66 (t,J=8.2 Hz, 1H), 2.22 (d, J=0.9 Hz, 3H). HPLC-MS (ESI+): m/z 287.1 [20%,(M³⁵Cl+Na)⁺], 267.2 [30%, (M³⁷Cl+H)⁺], 265.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[(1-methylethyl)sulfonamido]phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine(MA3-014-2)

This was prepared from MA2-092 (0.095 g) and MA3-010 (0.114 g) usingprocedure B (reaction time, 3 days) and isolated in the same way asMA2-030 to give the title compound MA3-016-3 as a white solid (0.114 g,62%). Mp: 233° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.83 (s, 1H,disappeared on D₂O shake), 9.19 (s, 1H disappeared on D₂O shake), 7.57(t, J=1.9 Hz, 1H), 7.34 (d, with unresolved fine coupling, J=8.0 Hz,1H), 7.26 (t, J=8.0 Hz, 1H), 6.90 (ddd, J=8.0, 2.0, 1.0 Hz, 1H),3.33-3.26 (m, 1H), 2.80 (t, J=7.6 Hz, 4H), 2.09-2.03 (m, 2H), 1.26 (d,J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z 369.1 [40%, (M³⁷Cl+H)⁺], 367.1 [100%,(M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3-(1,1-dimethylethylsulfinamido)phenyl]pyrimidine-4-amine(MA2-006)

The aniline MA1-098 (0.124 g) and DMAP (0.065 g) were dissolved in dryDCM (15 mL) and t-butylsulfinyl chloride (0.074 g) was added via asyringe at room temperature. The reaction mixture was stirred at roomtemperature for 1 h and then poured onto ice-water (10 mL). The mixturewas extracted with DCM (50 mL). The combined organic layers weresequentially washed with NaHCO₃ (50 mL) and brine (20 mL), dried(Na₂SO₄) and evaporated. The residue was purified via columnchromatography (SiO₂) eluting with hexanes/EtOAc (0:10 to 2:8 v/v) togive the title compound as a brown solid (0.144 g, 80%). Mp: 135° C.(dec). ¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (s, 1H, 30% reduced on D₂Oshake), 8.07 (s, 1H, disappeared on D₂O shake), 8.05 (d, J=0.8 Hz, 1H),7.43 (t, J=1.8 Hz, 1H), 7.25 (dt, J=8.2, 1.8 Hz, 1H), 7.20 (d, J=8.2 Hz,1H), 6.83 (dt, J=8.2, 1.8 Hz, 1H), 2.16 (d, J=0.8 Hz, 3H), 1.24 (s, 9H).HPLC-MS (ESI+): m/z 341.2 [40%, (M³⁷Cl+H)⁺], 339.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3-(aminophenyl)]pyrimidine-4-amine (MA1-098)

This was prepared from MA053 (0.240 g). A mixture of TFA:DCM (2:8, 3 mL)was added to MA1-053 (0.240 g) in a microwave vial equipped with amagnetic stirrer bar. The vial was heated in microwave reactor (BiotageInitiator) at 80° C. for 15 minutes and allowed to cool to roomtemperature. The DCM was removed under reduced pressure and the residuediluted with ethyl acetate (50 mL), washed with NaHCO₃ (aq., 20 mL) andwater (20 mL). The organic layer was dried (Na₂SO₄) and evaporated invacuo. The residue was purified by column chromatography (SiO₂, elutingwith DCM-MeOH, 0-10%) to provide the title compound MA1-098 as a yellowoil (129 mg, 78%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.59 (s, 1H, 30% reducedon D₂O shake), 7.98 (d, J=0.8 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.77-6.71(m, 2H), 6.37-6.32 (m, 1H), 5.11 (s, 2H), 2.12 (d, J=0.8 Hz, 3H).HPLC-MS (ESI+): m/z 237.1 [40%, (M³⁷Cl+H)⁺], 235.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)quinazoline-4-amine(MA2-084)

This was prepared from MA2-028 (0.199 g) and SG3-147 (0.214 g) usingprocedure B (reaction time, 3 h) and isolated in the same way as MA2-030to give the title compound MA2-084 as a white solid (0.267 g, 71%). Mp:220-223° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 10.43 (s, 1H,disappeared on D₂O shake), 8.60 (d, J=8.3 Hz, 1H), 8.29 (t, J=1.8 Hz,1H), 8.10 (d, with unresolved fine coupling, J=8.0 Hz, 1H), 7.93 (ddd,J=8.3, 7.1, 1.2 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.69 (ddd, J=8.3, 7.1,1.2 Hz, 1H), 7.66-7.58 (m, 3H, 1H disappeared on D₂O shake), 3.39-3.34(m, 1H, partially overlapped by the residual H₂O signal), 1.00 (d, J=6.5Hz, 6H). HPLC-MS (ESI+): m/z 379.1 [40%, (M³⁷Cl+H)⁺], 377.1 [100%,(M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3-(1,1-dimethylethyloxycarbonylamino)phenyl]-pyrimidine-4-amine(MA1-053)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.326 g) andN-Boc-m-phenylenediamine (0.416 g) using procedure A (reaction time, 16h) to give the title compound MA1-053 as a white solid (0.315 g, 46%).Mp: 250° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.41 (s, 1H, 30% reducedon D₂O shake), 8.87 (s, 1H, 90% reduced on D₂O shake), 8.03 (d, J=0.8Hz, 1H), 7.75 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H),7.13 (d, J=8.0 Hz, 1H), 2.15 (s, 3H), 1.48 (s, 9H). HPLC-MS (ESI+): m/z337.2 [40%, (M³⁷Cl+H)⁺], 335.2 [100%, (M³⁵Cl+H)]

2-Chloro-5-ethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)pyrimidine-4-amine(MA1-013)

This was prepared from MA1-012 (0.106 g) and SG1-147 (0.128 g) usingprocedure B (reaction time, 16 h) and isolated in the same way asMA2-030 to give the title compound MA1-013 as a white solid (0.099 g,46%). Mp: 260° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.12(s, 1H), 8.10 (t, J=1.8 Hz, 1H), 7.92 (d, with unresolved fine coupling,J=8.1 Hz, 1H), 7.61-7.55 (m, 2H, 1H disappeared on D₂O shake), 7.51 (d,with unresolved fine coupling, J=8.1 Hz, 1H), 3.48-3.40 (m, 1H), 2.64(q, J=7.4 Hz, 2H), 1.19 (t, J=7.4 Hz, 3H), 0.98 (d, J=6.5 Hz, 6H).HPLC-MS (ESI+): m/z 357.1 [40%, (M³⁷Cl+H)⁺], 355.1 [100%, (M³⁵Cl+H)⁺].

2,5-Dichloro-N⁴-[4-chloro-3-isopropoxyphenyl]pyrimidine-4-amine(MA1-088)

This was prepared from 2,4,5-trichloropyrimidine (0.115 g) and MA1-086(0.186 g) using procedure B (reaction time, 1.5 h) to give the titlecompound as a white solid (0.288 g, 92%). Mp: 120° C. (dec). ¹H NMR (400MHz, DMSO-d₆): δ 9.55 (s, 1H, disappeared on D₂O shake), 8.40 (s, 1H),7.51 (d, J=2.2 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.19 (dd, J=8.6, 2.2 Hz,1H), 4.59 (septet, J=6.0 Hz, 1H), 1.34 (d, J=6.0 Hz, 6H). HPLC-MS(ESI+): HPLC-MS (ESI+): m/z 336.1 [30%, (M³⁷Cl³⁷Cl³⁵Cl+H)⁺], 334.0 [95%,(M³⁷Cl³⁵Cl³⁵Cl+H)⁺], 332.1 [100%, (M³⁵Cl³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-bromo-N⁴-[4-chloro-3-methoxyphenyl]pyrimidine-4-amine(MA2-004)

This was prepared from 5-bromo-2,4-dichloropyrimidine (0.911 g) and3-methoxy-4-chloroaniline (0.662 g) using procedure B (reaction time, 1h) to give the title compound MA2-004 as a beige solid (1.37 g, 99%).Mp: 224° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (s, 1H, disappearedon D₂O shake), 8.50 (s, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.42 (d, J=8.6 Hz,1H), 7.26 (dd, J=8.6, 2.1 Hz, 1H), 3.84 (s, 3H). HPLC-MS (ESI+): m/z353.9 [10%, (M⁸¹Br³⁷Cl³⁷Cl+H)⁺], 351.9 [40%, (M⁸¹Br³⁷Cl³⁵Cl+H andM⁷⁹Br³⁷Cl³⁷Cl)⁺], 350.0 [100%, (M⁷⁹Br³⁷Cl³⁵C+H and M⁸¹Br³⁵Cl³⁵Cl)⁺],348.0 [55%, (M⁷⁹Br³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-(3-[(N-1-methylcyclopropyl)sulfamoyl]-4-chlorophenyl)pyrimidine-4-amine(MA5-014)

This was prepared from MA5-010 (0.207 g) and2,4-dichloro-5-methylpyrimidine (0.129 g) using procedure B (reactiontime, 24 h). After evaporation of the volatiles, the crude mixture wasdirectly absorbed on silica and the product was purified via columnchromatography (SiO₂) eluting with hexanes/EtOAc (2:8 to 1:1 v/v) togive the title compound MA5-014 as a white solid (0.181 g, 59%). Mp:230° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.49 (s, 1H, disappeared onD₂O shake), 8.99 (s, 1H, disappeared on D₂O shake), 8.09 (d, J=0.7 Hz,1H), 7.89 (d, J=2.4 Hz, 1H), 7.57 (dd, J=8.8, 2.4 Hz, 1H), 7.47 (d,J=8.8 Hz, 1H), 2.18 (s, 3H), 1.50 (s, 3H), 1.14-1.10 (m, 2H), 0.82-0.78(m, 2H). HPLC-MS (ESI+): m/z 389.1 [70%, (M³⁷C₃ ⁵Cl+H)⁺], 387.1 [100%,(M³⁵Cl³⁵Cl+H)⁺].

2-Chloro-5-ethoxycarbonyl-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-pyrimidine-4-amine(MA4-048)

This was prepared from MA2-010B2 (0.080 g) and2,4-dichloro-5-ethoxycarbonylpyrimidine (Combi-Blocks) (0.077 g) usingprocedure B (reaction time, 16 h) to give the title compound MA4-048 asyellow solid (0.112 g, 76%). Mp: 228° C. (dec). ¹H NMR (400 MHz,DMSO-d₆): δ 10.22 (s, 1H, disappeared on D₂O shake), 9.76 (s, 1H,disappeared on D₂O shake), 8.80 (s, 1H), 7.61 (brs, 1H), 7.36-7.24 (m,2H), 7.15-7.06 (m, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H),1.31 (s, 9H). HPLC-MS (ESI+): m/z 415.1 [40%, (M³⁷Cl+H)⁺], 413.1 [100%,(M³⁵Cl+H)⁺].

2-Chloro-5-methyl-N⁴-[3,5-bis-(cyclopropylsulfonamido)phenyl]pyrimidine-4-amine(MA4-056)

This was prepared from the aniline MA4-044 (0.100 g) and2,4-dichloro-5-methylpyrimidine (0.049 g) using procedure B (reactiontime, 3 days). The crude reaction mixture was dissolved in EtOAc (30 mL)and washed with water (20 mL). The title compound was purified (twice)via column chromatography (SiO₂) eluting with DCM/MeOH (10:0 to 9:1 v/v)to give the title compound MA4-056 as a yellow solid (0.054 g, 39%). Mp:228° C. (dec). ¹H NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 2H, disappeared onD₂O shake), 8.99 (s, 1H, disappeared on D₂O shake), 8.07 (d, J=0.9 Hz,1H), 7.30 (d, J=1.9 Hz, 2H), 6.90 (t, J=1.9 Hz, 1H), 2.71-2.66 (m, 2H),2.16 (s, 3H), 1.28-1.23 (m, 2H), 1.03-4.95 (m, 6H). HPLC-MS (ESI+): m/z460.1 [40%, (M³⁷Cl+H)⁺], 458.1 [100%, (M³⁵Cl+H)⁺].

2-Chloro-N⁴-[4-chloro-3-isopropoxyphenyl]-5-methylpyrimidine-4-amine(MA1-090)

This was prepared from 2,4-dichloro-5-methylpyrimidine (0.163 g) andMA1-086 (0.186 g) using procedure B (reaction time, 2.5 days) to givethe title compound as a yellow solid (0.180 g, 58%). ¹H NMR (400 MHz,DMSO-d₆): δ 8.90 (s, 1H), 8.08 (d, J=0.7 Hz, 1H), 7.60 (d, J=2.3 Hz,1H), 7.37 (d, J=8.6 Hz, 1H), 7.23 (dd, J=8.6, 2.3 Hz, 1H), 4.62-4.51 (m,1H), 2.17 (d, J=0.7 Hz, 3H), 1.35 (d, J=6.0 Hz, 6H). HPLC-MS (ESI−): m/z314.1 [60%, (M³⁷Cl³⁵Cl—H)⁺], 312.1 [95%, (M³⁵Cl³⁵Cl—H)⁺].

Example 3: Synthesis of A-Ring and B-Ring Precursors

The following nitrobenzenesulfonamides were prepared using thepreviously reported method (Lawrence, et al., Synthesis and biologicalevaluation of naphthoquinone analogs as a novel class of proteasomeinhibitors. Bioorg Med Chem 2010, 18, 5576-92).

Method a:

To a mixture of nitrobenzenesulfonyl chloride (1.0 equiv.) in THF (0.45M) was added amine (3.0 equiv.). The solution was stirred at roomtemperature for 30 min. The pH was adjusted to pH 2 by the addition ofHCl (1 M, aq.) at 0° C. The solvent was removed and the resulting solidwas triturated using EtOAc/hexanes, washed with water, and dried.

Method a1:

Substituted aniline (1 equiv.) was dissolved in dry DCM (0.1M to 1 M),pyridine (1.5-5 eq.) and the solution was cooled to 0° C.Arylsulfonylchloride (2.5 equiv.) was added dropwise and the mixture wasallowed to warm to room temperature and stirred overnight. The reactionmixture was cooled in an ice-bath and 1M HCl solution was added until pH7. DCM was added to the mixture and the organic layer was separated,evaporated and dried (Na₂SO₄) to provide the title compound.

Method b:

To a solution of nitroarene (1.0 equiv.) in EtOH or MeOH (deoxygenatedwith bubbled Argon) was added Pd/C (10%) and hydrazine monohydrate 65%(3.0 equiv.) under Argon. The solution was stirred and heated at refluxfor the indicated time. The reaction mixture was filtered over Celite,and the filtrate concentrated under reduced pressure.

Method c:

A solution of nitroarene (1.0 equiv.) in MeOH (deoxygenated with bubbledargon) was cooled in an ice-bath and ammonium formate (3 equiv.) wasadded. After ˜5 minutes Pd/C (10%, 0.1 equiv.) was added and reactionwas stirred at 0° C. for 30 minutes and at room temperature overnight.The reaction mixture was filtered over Celite, and the filtrateconcentrated under reduced pressure. The residue was redissolved inEtOAc and washed with water. The organic layer was separated, dried(Na₂SO₄) and concentrated to give the product.

N-(Dimethylethyl)-3-nitrobenzenesulfonamide (SG1-133)

This was prepared from 3-nitrobenzenesulfonyl chloride (3.00 g) andtert-butylamine (4.27 mL) using the general method a and provided thetitle compound as a white solid (2.84 g, 66%). Mp: 103-104° C.(Campbell, et al., Derivatives of the lower aliphatic amines. Proc.Indiana Acad. Sci. 1948, 57, 97-100; 99-100° C.). ¹H NMR (400 MHz,CDCl₃) δ: 8.74 (t, J=1.9 Hz, 1H), 8.40 (ddd, J=8.0, 1.9, 1.0 Hz, 1H),8.23 (ddd, J=8.0, 1.9, 1.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 4.84 (brs,1H), 1.27 (s, 9H). HPLC-MS (ESI+): m/z 539.1 [40%, (2M+Na)⁺], 281.0[45%, (M+Na)⁺], 276.2 [100%, (M+NH₄)⁺].

N-Methylethyl-3-nitrobenzenesulfonamide (SG1-143)

This was prepared from 3-nitrobenzenesulfonyl chloride (3.00 g) andisopropylamine (3.32 mL) using the general method a and provided thetitle compound as an off-white solid (2.85 g, 86%). Mp: 64-65° C.(Campbell et al., 64-65° C.). ¹H NMR (400 MHz, DMSO-do) δ: 8.52 (t,J=1.9 Hz, 1H), 8.45 (ddd, J=8.0, 1.9, 1.0 Hz, 1H), 8.21 (ddd, J=8.0,1.9, 1.0 Hz, 1H), 7.97 (brd, J=6.8 Hz, 1H, disappeared on D₂O shake),7.88 (t, J=8.0 Hz, 1H), 3.28 (octet, J=6.8 Hz, 1H), 0.94 (d, J=6.8 Hz,6H). HPLC-MS (ESI+): m/z 511.1 [40%, (2M+Na)⁺], 267.2 [100%, (M+Na)⁺].

N-Dimethylethyl-4-nitrobenzenesulfonamide (SG1-174)

This was prepared from 4-nitrobenzenesulfonyl chloride (10.00 g) andt-butylamine (14.22 mL) using the general method a and provided thetitle compound as a tangerine solid (10.64 g, 91%). Mp: 103-104° C.(lit.³ 104-105° C.). ¹H NMR (400 MHz, CDCl₃) δ: 8.34 (d, J=9.0 Hz, 2H),8.09 (d, J=9.0 Hz, 2H), 5.01 (s, 1H), 1.25 (s, 9H). HPLC-MS (ESI+): m/z281.1 [100%, (M+Na)⁺].

N-(1-Hydroxy-2-methylpropan-2-yl)-3-nitrobenzenesulfonamide (SG2-076)

This was prepared from 3-nitrobenzenesulfonyl chloride (1.00 g) and2-amino-2-methyl-1-propanol (1.21 g) using the general method a toprovide the title compound as a white solid (0.510 g, 41%). Mp: 109-111°C. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.59 (t, J=1.9 Hz, 1H), 8.42 (ddd,J=8.0, 1.9, 1.0 Hz, 1H), 8.23 (ddd, J=8.0, 1.9, 1.0 Hz, 1H), 7.85 (t,J=8.0 Hz, 1H), 7.75 (s, 1H, disappeared on D₂O shake), 4.78 (t, J=5.7Hz, 1H, disappeared on D₂O shake), 3.18 (d, J=5.7 Hz, 2H), 1.01 (s, 6H).HPLC-MS (ESI+): m/z 571.1 [90%, (2M+Na)⁺], 297.0 [100%, (M+Na)⁺].

N-(1,1-Dimethylethyl)-2-methyl-5-nitrobenzenesulfonamide (SG2-097)

This was prepared from 2-methyl-5-nitrobenzenesulfonyl chloride (2.00 g)and tert-butylamine (2.68 mL) using the general method a to provide thetitle compound⁵ as a light brown solid (2.01 g, 87%). Mp: 128-129° C.(lit.⁵ Mp: 127-129° C.). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.58 (d, J=2.5 Hz,1H), 8.33 (dd, J=8.4, 2.5 Hz, 1H), 7.92 (s, 1H, reduced by 50% on D₂Oshake), 7.68 (d, J=8.4 Hz, 1H), 2.69 (s, 1H), 1.10 (s, 3H). HPLC-MS(ESI+): m/z 567.2 [60%, (2M+Na)⁺], 297.0 [100%, (M+Na)⁺], 290.2 [50%,(M+NH₄)⁺].

N-(1,1-Dimethylethyl)-2-chloro-5-nitrobenzenesulfonamide (SG3-137)

This was prepared from SG3-128 (0.750 g) and tert-butylamine (0.923 mL)using the general method a to provide the title compound as an off-whitesolid (0.694 g, 81%). Mp: 202° C. (dec). ¹H NMR (400 MHz, CDCl₃) δ: 8.97(d, J=2.7 Hz, 1H), 8.34 (dd, J=8.7, 2.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H),5.01 (s, 1H), 1.25 (s, 9H). HPLC-MS (ESI+): m/z 609.1 [50%,(M³⁷Cl+M³⁵Cl+H)⁺], 607.1 [80%, (2M³⁵Cl+H)⁺], 317.0 [30%, (M³⁷Cl+H)⁺],315.1 [100%, (M³⁵Cl+H)⁺].

3-Amino-N-(dimethylethyl)benzenesulfonamide (SG1-137)

This was prepared from SG1-133 (2.50 g), hydrazine monohydrate 65% (1.39mL), Pd/C (0.500 g), and EtOH (40 mL) using the general method b(reaction time, 3 h) to provide the title compound as a white solid(1.74 g, 79%). Mp: 140° C. ¹H NMR (400 MHz, DMSO-d₆) δ:7.29 (s, 1H),7.13 (t, J=7.9 Hz, 1H), 6.99 (t, J=2.0 Hz, 1H), 6.90 (ddd, J=7.9, 2.0,0.9 Hz, 1H), 6.67 (ddd, J=7.9, 2.0, 0.9 Hz, 1H), 5.50 (s, 2H), 1.07 (s,9H). HPLC-MS (ESI+): m/z 479.3 [20%, (2M+Na)⁺], 173.2 [100%,(M-tBu+H)²⁺].

3-Amino-N-(methylethyl)benzenesulfonamide (SG1-147)

This was prepared from SG1-143 (2.50 g), hydrazine monohydrate 65% (1.47mL), Pd/C (0.544 g), and EtOH (40 mL) using the general method b(reaction time, 2 h) to provide the title compound as a white solid(1.92 g, 88%). Mp: 94-96° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.34 (d, J=6.8Hz, 1H, disappeared on D₂O shake), 7.15 (t, J=7.9 Hz, 1H), 6.96 (t,J=2.2 Hz, 1H), 6.86 (ddd, J=7.9, 2.2, 0.8 Hz, 1H), 6.70 (ddd, J=7.9,2.2, 0.8 Hz, 1H), 5.54 (s, 2H, disappeared on D₂O shake), 3.17 (octet,J=6.8 Hz, 1H), 0.92 (d, J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z 429.2 [20%,(2M+H)⁺], 215.1 [100%, (M+H)⁺].

4-Amino-N-(dimethylethyl)benzenesulfonamide (SG1-177)

This was prepared from SG1-174 (10.64 g), hydrazine monohydrate 65%(5.92 mL), Pd/C (1.00 g), and EtOH (80 mL) using the general method b(reaction time, 4.5 h) to provide the title compound as a lighttangerine solid (8.50 g, 90%). Mp: 122-123° C. ¹H NMR (400 MHz, DMSO-d₆)δ: 7.40 (d, J=8.7 Hz, 2H), 6.98 (s, 1H, disappeared on D₂O shake), 6.56(d, J=8.7 Hz, 2H), 5.83 (s, 2H, disappeared on D₂O shake), 1.03 (s, 9H).HPLC-MS (ESI+): m/z 479.3 [100%, (2M+Na)⁺], 229.2 [25%, (M+H)⁺], 173.2[60%, (M-tBu+H)⁺].

3-Amino-N-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide⁶ (SG2-079)

This was prepared from SG2-076 (1.90 g), hydrazine monohydrate 65%(0.995 mL), Pd/C (0.250 g), and EtOH (30 mL) using the general method b(reaction time, 3 h) to provide the title compound as a yellow solid(U.S. Pat. No. 7,378,417). Mp: 68-71° C. ¹H NMR (400 MHz, DMSO-d₆) δ:7.13 (t, J=7.8 Hz, 1H), 7.06 (s, 1H, disappeared on D₂O shake), 6.99 (t,J=1.9 Hz, 1H), 6.90 (ddd, J=7.8, 1.9, 0.8 Hz, 1H), 6.68 (ddd, J=7.8,1.9, 0.8 Hz, 1H), 5.50 (s, 2H, disappeared on D₂O shake), 4.71 (t, J=5.8Hz, 1H, disappeared on D₂O shake), 3.16 (d, J=5.8 Hz, 2H), 0.99 (s, 6H).HPLC-MS (ESI+): m/z 511.1 [40%, (2M+Na)⁺], 245.2 [100%, (M+H)⁺], 173.1[95%, (M-CMe₂CH₂OH+H)⁺].

5-Amino-N-(1,1-dimethylethyl)-2-methylbenzenesulfonamide (SG2-100)

This was prepared from SG2-097 (1.91 g), hydrazine monohydrate (65%,1.57 mL), palladium (10%) on carbon (0.500 g), and EtOH (35 mL) usingthe general method b (reaction time, 3 h) to provide the title compoundas an off-white solid (1.63 g, 96%). Mp: 136-137° C. ¹H NMR (400 MHz,DMSO-d₆) δ: 7.19 (s, 1H, disappeared on D₂O shake), 7.14 (d, J=2.5 Hz,1H), 6.94 (d, J=8.1 Hz, 1H), 6.60 (dd, J=8.1, 2.5 Hz, 1H), 5.25 (s, 2H,disappeared on D₂O shake), 2.36 (s, 3H), 1.07 (s, 9H). HPLC-MS (ESI+):m/z 485.3 [20%, (2M+Na)⁺], 187.2 [100%, (M-tBu+H)²⁺].

N-(5-Aminophenyl)-3-N,N-dimethylsulfamide (SG3-033-01)

This was prepared from SG3-028 (1.40 g), hydrazine monohydrate 65% (1.28mL), palladium (10%) on carbon (0.250 g), and EtOH (25 mL) using thegeneral method b (reaction time, 1.5 h). The resulting oil was purifiedvia column chromatography (SiO₂) eluting with hexanes/EtOAc (1:9 to 1:1v/v) to give the title compound as an off-white solid (0.941 g, 77%).Mp: 135° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.51 (s, 1H, disappearedon D₂O shake), 6.86 (t, J=7.9 Hz, 1H), 6.43 (s, 1H), 6.33 (d, J=7.9 Hz,1H), 6.22 (d, J=7.9 Hz, 1H), 5.10 (s, 2H, disappeared on D₂O shake),2.66 (s, 6H). HPLC-MS (ESI+): m/z 216.2 [100%, (M+H)⁺].

5-Amino-N-(1,1-dimethylethyl)-2-chlorobenzenesulfonamide (SG3-142)

A mixture of SG3-137 (0.750 g), iron(III) chloride hexahydrate (0.021g), charcoal (0.200 g), and MeOH (6 mL) was heated at reflux for 10 min.Hydrazine monohydrate (65%, 0.766 mL) was added and the reaction mixturewas further heated at reflux for 2 h. The mixture was filtered overCelite and the filtrate concentrated under reduced pressure. Theresulting residue was dissolved in EtOAc (8 mL) and washed with water(1×10 mL) and brine (1×10 mL). The organic layer was dried (Na₂SO₄),concentrated under reduced pressure, and the resulting residue purifiedvia column chromatography (SiO₂) eluting with hexanes/EtOAc (0:10 to 4:6v/v) to give the title compound as a yellow solid (0.314 g, 47%). Mp:223° C. (dec). ¹H NMR (400 MHz, CDCl₃) δ: 7.49 (d, J=2.8 Hz, 1H), 7.25(d, J=7.8 Hz, 4H), 6.81 (dd, J=7.8, 2.8 Hz, 1H), 4.99 (s, 1H), 1.22 (s,9H). HPLC-MS (ESI+): m/z 547.2 [20%, (2M+Na)⁺], 209.1 [40%,(M³⁷Cl-tBu+H)²⁺], 207.1 [100%, (M³⁵Cl-tBu+H)²⁺].

N-(5-Amino-2-chlorophenyl)cyclopropanesulfonamide (SG2-159)

This was prepared from SG2-152 (3.23 g), hydrazine monohydrate 65% (3.93mL), Pd/C (0.750 g), and EtOH (45 mL) using the general method b(reaction time, 8 h) to provide the title compound as an off-white solid(1.86 g, 65%). Mp: 93-94° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (s, 1H,disappeared on D₂O shake), 7.04 (d, J=8.6 Hz, 1H), 6.68 (d, J=2.7 Hz,1H), 6.39 (dd, J=8.6, 2.7 Hz, 1H), 5.33 (s, 2H, disappeared on D₂Oshake), 2.56 (tt, J=7.8, 4.9 Hz, 1H), 0.96-0.83 (m, 4H). HPLC-MS (ESI+):m/z 249.1 [40%, (M³⁷Cl+H)⁻], 247.1 [100%, (M³⁵Cl+H)⁺].

N-(5-Amino-2-methylphenyl)-2-methylpropane-2-sulfonamide (SG3-124)

This was prepared from SG3-123 (0.410 g), hydrazine monohydrate (65%,0.337 mL), Palladium (10%) on carbon (0.100 g), and MeOH (10 mL) usingthe general method b (reaction time, 15 h). The resulting residue wastriturated using EtOAc/hexanes to provide the title compound as anoff-white solid (0.338 g, 93%). Mp: 170° C. (dec). ¹H NMR (400 MHz,CDCl₃) δ: 7.17 (d, J=2.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.49 (dd,J=8.1, 2.1 Hz, 1H), 5.91 (s, 1H), 2.20 (s, 3H), 1.42 (s, 9H). HPLC-MS(ESI+): m/z 485.3 [20%, (2M+H)⁺], 243.2 [100%, (M+H)⁺].

N-(5-Nitrophenyl)-3-N,N-dimethylsulfamide (SG3-028)

To a mixture of nitroaniline (1.00 g, 7.24 mmol), pyridine (1.75 mL,21.72 mmol), and DCM (15 mL) was added dimethylsulfamoyl chloride (1.17mL, 10.86 mmol). The solution was stirred at room temperature for 3.5 d.The solvent was removed and EtOAc (20 mL) was added. The organic layerwas washed with HCl (1 M aq. solution, 2×25 mL), water (2×25 mL), andbrine (2×25 mL), dried (Na₂SO₄), and concentrated under reduced pressureto give the title compound as a tangerine-colored solid (1.53 g, 86%).Mp: 121-126° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.52 (s, 1H,disappeared on D₂O shake), 7.98 (t, J=2.1 Hz, 1H), 7.87 (dt, J=7.8, 2.1Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.57-7.54 (m, 1H), 2.72 (s, 6H).HPLC-MS (ESI+): m/z 268.1 [100%, (M+Na)⁺], 246.2 [90%, (M+H)⁺].

4-Chloro-3,5-dimethoxyaniline (SG2-062-01)

This was prepared using the previously reported method (US2012/0149737). A mixture of 3,5-dimethoxyaniline (2.67 g, 20 mmol),acetic acid (25 mL), and N-chlorosuccinimide (3.37 g, 22 mmol) wasstirred at room temperature for 4.5 h. Water (50 mL) and EtOAc (50 mL)were added. The organic layer was washed with brine (1×50 mL), dried(Na₂SO₄), and concentrated under reduced pressure. The resulting residuewas purified via column chromatography (SiO₂) eluting with hexanes/EtOAc(gradient: 100% hexanes to 30% ethyl acetate in hexanes) to give thetitle compound as a brown solid (0.594 g, 16%). Mp: 153° C. (dec). ¹HNMR (400 MHz, DMSO-d₆) δ: 5.94 (s, 2H), 5.28 (s, 2H, disappeared on D₂Oshake), 3.69 (s, 6H). HPLC-MS (ESI+): m/z 190.1 [30%, (M³⁷Cl+H)⁺], 188.1[100%, (M³⁵Cl+H)⁺].

5-Carboxamide-2,4-dichloropyrimidine (SG2-138)

To a solution of PE1-028B3 (1.00 g, 4.73 mmol) in DCM (2 mL) was addedNH₄OH (30% aq. solution, 2.51 mL, 18.92 mmol) slowly at 0° C. Water (1mL) was added and the mixture stirred for 5 min and the precipitatefiltered. The resulting solid was washed with water (1×10 mL) and driedto give the title compound as a pale yellow solid (0.730 g, 80%). Mp:194° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.88 (s, 1H), 8.18 (s, 1H),8.05 (s, 1H). HPLC-MS (ESI+): m/z 216.1 [40%, (M³⁷Cl+Na)⁺], 214.1 [80%,(M³⁵Cl+Na)⁺], 194.1 [60%, (M³⁷Cl+H)⁺], 192.1 [100%, (M³⁵Cl+H)⁺].

N-(2-Chloro-5-nitrophenyl)cyclopropanesulfonamide (SG2-152)

Cyclopropanesulfonyl chloride (2.66 mL, 26.08 mmol) was added to amixture of 2-chloro-5-nitroaniline (3.00 g, 17.38 mmol), pyridine (4.21mL, 52.15 mmol), and DCM (35 mL) in an Ace pressure tube. The mixturewas heated at 150° C. for 4 d. The solution was poured into a separatoryfunnel and EtOAc (50 mL) was added. The organic layer was washed with 1M HCl (2×25 mL), water (2×25 mL), and brine (2×25 mL), dried (Na₂SO₄),and concentrated under reduced pressure. The resulting solid wastriturated using EtOAc/hexanes and provided the title compound as atangerine-colored solid (3.23 g, 67%). Mp: 133-137° C. ¹H NMR (400 MHz,CDCl₃) δ: 8.55 (d, J=2.6 Hz, 1H), 7.98 (dd, J=8.8, 2.6 Hz, 1H), 7.60 (d,J=8.8 Hz, 1H), 6.96 (s, 1H, disappeared on D₂O shake), 2.57 (tt, J=8.0,4.8 Hz, 1H), 1.35-1.24 (m, 2H), 1.14-1.03 (m, 2H). HPLC-MS (ESI+): m/z301.1 [30%, (M³⁷Cl+Na)⁺], 299.1 [100%, (M³⁵Cl+Na)⁺]. HPLC-MS (ESI−): m/z277.0 [30%, (M³⁷Cl—H)⁻], 275.1 [100%, (M³⁵Cl—H)⁻].

The following anilines were prepared using the previously reportedmethod (U.S. Pat. No. 8,563,542). Method c: To a mixture of benzoic acid(1.0 equiv.), TBTU (1.1 equiv.), and DCM was added DIPEA (2.0 equiv.).The solution was stirred at room temperature for 30 min followed by theaddition of 1-methylpiperidin-4-amine (1.2 equiv.). The reaction mixturewas further stirred at room temperature overnight. Work-up and productisolation procedure are described below.

4-Amino-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (SG3-016)

This was prepared from 4-amino-3-methoxybenzoic acid (1.06 g), TBTU(2.25 g), DIPEA (2.22 mL), 1-methylpiperidin-4-amine (0.960 mL), and DCM(50 mL) using the general method c. Water (50 mL) and DCM (50 mL) wereadded. The aqueous layer was concentrated under reduced pressure andsodium hydroxide (1 M aq. solution, 50 mL) added. The mixture wasextracted with DCM (50 mL). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure to give the title compound⁹ as anoff-white solid (0.987 g, 59%). Mp: 215° C. (dec). ¹H NMR (400 MHz,DMSO-d₆) δ: 7.79 (d, J=7.8 Hz, 1H), 7.29-7.24 (m, 2H), 6.57 (d, J=8.6Hz, 1H), 5.21 (s, 2H, disappeared on D₂O shake), 3.78 (s, 3H), 3.74-3.59(m, 1H), 2.78-2.70 (brd, J=11.4 Hz, 2H), 2.14 (s, 3H), 1.95-1.84 (brt,J=11.4 Hz, 2H), 1.74-1.65 (brd, J=12.1, 3.3 Hz, 2H), 1.53 (qd, J=12.1,3.3 Hz, 2H). HPLC-MS (ESI+): m/z 264.2 [100%, (M+H)⁺].

4-Amino-N-(1-methylpiperidin-4-yl)benzamide (SG3-051)

This was prepared from 4-aminobenzoic acid (1.00 g), TBTU (2.58 g),DIPEA (2.54 mL), 1-methylpiperidin-4-amine (1.10 mL), and DCM (50 mL)using the general method c. The solvent was removed and the resultingoil was partitioned between water (50 mL) and DCM (50 mL). The aqueouslayer was concentrated under reduced pressure, 1 M (50 mL of a 1 M aq.solution) was added, and the mixture stirred at room temperature for 1h. The resulting precipitate was filtered, washed with water (3×20 mL)and DCM (3×20 mL), and dried (Na₂SO₄) to give the title compound (Qin,et al., Synthesis and biological evaluation of 2,4-diaminopyrimidines asselective Aurora A kinase inhibitors. Eur J Med Chem 2015, 95, 174-84)as an off-white solid (1.41 g, 83%). Mp: 206° C. (dec). ¹H NMR (400 MHz,DMSO-d₆) δ: 7.72 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 6.51 (d,J=8.6 Hz, 2H), 5.57 (s, 2H), 3.73-3.59 (m, 1H), 2.78-2.69 (brd, J=11.6Hz, 2H), 2.14 (s, 3H), 1.94-1.84 (t, J=11.6 Hz, 2H), 1.74-1.64 (d,J=12.2 Hz, 2H), 1.53 (qd, J=12.2, 3.8 Hz, 2H). HPLC-MS (ESI+): m/z 234.2[100%₀, (M+H)⁺].

4-Amino-2-fluoro-N-(1-methylpiperidin-4-yl)benzamide (SG3-153)

This was prepared from 4-amino-2-fluorobenzoic acid (0.700 g), TBTU(1.59 g), DIPEA (1.57 mL), 1-methylpiperidin-4-amine (0.680 mL), and DCM(18 mL) using the general method c. The solvent was removed and theresulting oil was stirred in NaOH (1 M aq. solution, 50 mL) at roomtemperature for 30 min. The aqueous layer was extracted with DCM (1×50mL) and EtOAc (1×50 mL). The organic layers were combined, dried(Na₂SO₄), and concentrated under reduced pressure. The resulting solidwas recrystallized from EtOH/hexanes to provide the title compound as anoff-white solid (0.967 g, 85%). Mp: 202° C. (dec). 1H NMR (400 MHz,DMSO-d₆) δ: 7.41-7.36 (m, 1H), 7.34 (t, J=8.8 Hz, 1H), 6.35 (dd, J=8.5,2.0 Hz, 1H), 6.25 (dd, J=14.2, 2.0 Hz, 1H), 5.87 (s, 2H, disappeared onD₂O shake), 3.71-3.57 (m, 1H), 2.67 (d, J=11.6 Hz, 2H), 2.12 (s, 3H),1.92 (t, J=10.6 Hz, 2H), 1.70 (d, J=10.6 Hz, 2H), 1.49 (qd, J=11.6, 3.5Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −112.88. HPLC-MS (ESI+): m/z252.3 [100%, (M+H)⁺].

1,1-Dimethylethyl 4-chloro-3-nitrophenylcarbamate (SG3-084)

This was prepared using the reported procedure of Sloss et al. (US2009/0270418) 4-Chloro-3-nitroaniline (5.00 g, 28.97 mmol) anddi-tert-butyl carbonate (10.12 g, 46.36 mmol) were dissolved in dry THF(20 mL). The mixture was stirred and heated at reflux for 20 h. Thesolvent was removed and the yellow oil was triturated usingEtOAc/hexanes to give the title compound as a yellow solid (6.18 g,78%). Mp: 103° C. (dec). ¹H NMR (400 MHz, CDCl₃) δ: 8.06 (d, J=2.3 Hz,1H), 7.46 (dd, J=8.7, 2.3 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.64 (s, 1H),1.52 (s, 9H). HPLC-MS (ESI+): m/z 297.1 [30%, (M³⁷Cl+H)⁺], 295.1 [100%,(M³⁵Cl+H)⁺].

tert-Butyl 3-amino-4-chlorophenylcarbamate (SG3-085)

This was prepared using the reported procedure of Sloss et al. Thenitroarene SG3-084 (6.18 g, 22.66 mmol), iron(III) chloride hexahydrate(0.183 g, 0.679 mmol), and activated carbon (1 g) were combined in MeOH(50 mL) and stirred at reflux for 10 min. Hydrazine hydrate (6.78 mL,90.65 mmol) was added slowly and the mixture was stirred at reflux for 1h. Upon cooling to room temperature, the solution was filtered over abed of Celite and concentrated under reduced pressure. The resultingresidue was dissolved in EtOAc (80 mL) and washed with water (80 mL) andbrine (80 mL). The organic layer was dried (Na₂SO₄) and concentratedunder reduced pressure. The resulting solid was triturated usingEtOAc/hexanes to give the title compound as a white solid (4.74 g, 86%).Mp: 139-140° C. ¹H NMR (400 MHz, CDCl₃) δ: 7.15 (s, 1H), 7.12 (d, J=8.6Hz, 1H), 6.57 (dd, J=8.6, 2.5 Hz, 1H), 6.42 (s, 1H, disappeared on D₂Oshake), 1.50 (s, 9H). HPLC-MS (ESI+): m/z 509.2 [10%, (M³⁷Cl+M³⁵Cl+H)⁺],507.2 [15%, (2M³⁵Cl+H)⁻], 265.1 [10%, (M³⁵Cl+H)⁺], 189.2 [100%,(M³⁷Cl-tBu+H)²⁺], 187.2 [100%, (M³⁵Cl-tBu+H)²⁺].

1,1-Dimethylethyl4-chloro-3-(1,1-dimethylethylsulfinamido)phenylcarbamate (SG3-133)

To a solution of SG3-085 (2.43 g, 10 mmol) and pyridine (2.42 mL, 30mmol) in DCM (5 mL) was added a solution of t-butylsulfinyl chloride(1.23 mL, 10 mmol) in DCM (5 mL) dropwise at 0° C. under Argon. Themixture was stirred at 0° C. for 2 h, then warmed to room temperatureand further stirred for 5 h. The reaction mixture was diluted with EtOAc(100 mL) and washed with 1 M HCl (1×50 mL), water (1×50 mL), and brine(1×50 mL). The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure. The resulting residue was purified via columnchromatography (SiO₂) eluting with hexanes/EtOAc (0:10 to 3:7 v/v) togive the title compound as a light yellow foam (2.81 g, 81%). Mp: 124°C. (dec). ¹H NMR (400 MHz, CDCl₃) δ: 7.41 (d, J=2.4 Hz, 1H), 7.21 (d,J=8.8 Hz, 1H), 6.93 (brd, J=8.8 Hz, 1H), 6.50 (brs, 1H), 6.06 (brs, 1H),1.51 (s, 9H), 1.35 (s, 9H). HPLC-MS (ESI+): m/z 717.2 [80%,(M³⁷Cl+M³⁵Cl+H)⁻], 715.2 [70%, (2M³⁵Cl+H)⁺], 371.2 [50%, (M³⁷Cl+H)⁺],369.2 [100%, (M³⁵Cl+H)⁺].

N-(5-Amino-2-chlorophenyl)-2-methylpropane-2-sulfonamide (SG3-105)

A solution of SG3-088 (1.28 g, 3.52 mmol) in TFA/DCM (1:1, 20 mL) wasstirred for 2 h at room temperature. The mixture was concentrated underreduced pressure. The pH was adjusted to pH 12 by the addition of NaOH(1 M, aq.) and extracted with EtOAc (2×20 mL). The combined organiclayers were washed with water (1×20 mL) and brine (1×20 mL), dried(Na₂SO₄), and concentrated under reduced pressure. The resulting solidwas triturated using EtOAc/hexanes to provide the title compound as alight brown solid (0.902 g, 97%). Mp: 124-125° C. ¹H NMR (400 MHz,CDCl₃) δ: 7.23 (d, J=2.4 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.50 (s, 1H),6.42 (dd, J.=8.6, 2.4 Hz, 1H), 1.41 (s, 9H). HPLC-MS (ESI+): m/z 527.2[30%, (2M³⁷Cl+H)⁺], 525.2 [40%, (2M³⁵Cl+H)⁺], 265.2 [40%, (M³⁷Cl+H)⁺],263.2 [100%, (M³⁵Cl+H)⁺].

2-Methyl-N-(2-methyl-5-nitrophenyl)propane-2-sulfinamide (SG3-115)

To a solution of 2-methyl-5-nitroaniline (0.152 g, 1 mmol) and pyridine(0.242 mL, 3 mml) in DCM (1 mL) was added a solution of t-butylsulfinylchloride (0.185 mL, 1.5 mmol) at room temperature under Argon. Themixture was stirred overnight at room temperature. The reaction mixturewas diluted with EtOAc (10 mL) and washed with HCl (1 M aq. solution,1×10 mL), water (1×10 mL), and brine (1×10 mL). The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. The resultingresidue was purified via column chromatography (SiO₂) eluting withhexanes/EtOAc (0:10 to 4:6 v/v) to give the title compound as a lightyellow solid (2.81 g, 81%). Mp: 169° C. (dec). ¹H NMR (400 MHz, CDCl₃)δ: 8.02 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.2, 2.2 Hz, 1H), 7.30 (d, J=8.2Hz, 1H), 5.37 (s, 1H), 2.36 (s, 3H), 1.39 (s, 9H). HPLC-MS (ESI+): m/z532.2 [40%, (2M+Na)⁺], 513.2 [100%, (2M+H)⁺], 257.2 [40%, (M+H)⁺].

2-Methyl-N-(2-methyl-5-nitrophenyl)propane-2-sulfonamide (SG3-123)

To a solution of SG3-115 (0.450 g, 1.76 mmol) in DCM (5 mL) was addedm-CPBA (65%, 0.433 g, 1.76 mmol) under Argon. The mixture was stirred atroom temperature for 14 h. The reaction mixture was diluted with DCM (50mL) and washed with saturated NaHCO₃ (2×50 mL) and brine (1×50 mL). Theorganic layer was dried (Na₂SO₄) and concentrated under reducedpressure. The resulting solid was triturated using EtOAc/hexanes to givethe title compound as a yellow solid (0.421 g, 88%). Mp: 207° C. (dec).¹H NMR (400 MHz, CDCl₃) δ: 8.51 (d, J=2.3 Hz, 1H), 7.91 (dd, J=8.4, 2.3Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 5.99 (s, 1H), 2.43 (s, 3H), 1.48 (s,9H). HPLC-MS (ESI+): m/z 567.2 [80%, (2M+Na)⁺], 295.1 [100%, (M+Na)⁺].

2-Chloro-5-nitrobenzene-1-sulfonyl chloride (SG3-128)

SG3-128 was prepared using the method previously reported by Goldfarband Berk. (New Compounds. Derivatives of 2,5-Diaminobenzenesulfonamide.J. am. Chem. Soc. 1943, 65, 738-739). A mixture of 4-chloronitrobenzene(3.94 g, 25 mmol) and chlorosulfonic acid (8.31 mL, 125 mmol) wasstirred and heated overnight at 120° C. The solution was cooled andpoured into crushed iced in an ice bath and the precipitate filtered.Recrystallization of the resulting solid from carbon tetrachloride(CAUTION) provided the title compound as a light brown solid (0.342 g,14%). Mp: 87-88° C. (lit. Mp 85-87° C.). ¹H NMR (400 MHz, CDCl₃) δ: 9.01(d, J=2.6 Hz, 1H), 8.51 (dd, J=8.7, 2.6 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H).

1-(4-Methylpiperazin-1-yl)-2-(4-nitrophenyl)ethanone (SG3-143)

To a mixture of 4-nitrophenylacetic acid (5.00 g, 27.60 mmol),carbonyldiimidazole (4.48 g, 27.60 mmol), and THF (28 mL) was added1-methylpiperazine (3.06 mL, 27.60 mmol). The solution was stirred for 2h at room temperature. The solvent was removed and EtOAc (100 mL) addedand washed with water (2×50 mL). The combined aqueous layers wereextracted with EtOAc (2×50 mL) and DCM (1×50 mL). The organic layerswere combined, dried (Na₂SO₄), and concentrated under reduced pressure.The resulting solid was recrystallized from EtOH/hexanes to provide thetitle compound (WO2005/042518) as a tangerine-colored solid (6.017 g,83%). Mp: 176° C. (dec). ¹H NMR (400 MHz, CDCl₃) δ: 8.19 (d, J=8.8 Hz,2H), 7.41 (d, J=8.8 Hz, 2H), 3.81 (s, 2H), 3.66 (t, J=5.0 Hz, 2H), 3.50(t, J=5.0 Hz, 2H), 2.39 (t, J=5.1 Hz, 2H), 2.32 (t, J=5.1 Hz, 2H), 2.29(s, 3H). HPLC-MS (ESI+): m/z 264.2 [100%, (M+H)⁺].

2-(4-Aminophenyl)-1-(4-methylpiperazin-1-yl)ethanone (SG3-144)

To a solution of SG3-143 (5.88 g, 22.36 mmol) in MeOH (25 mL,deoxygenated with Argon gas) was added Pd/C (10%, 0.500 g). A balloon ofhydrogen gas was attached to the flask via a septum cap. The mixture wasstirred at room temperature for 29 h. The reaction mixture was filteredover Celite and the filtrate concentrated under reduced pressure toprovide the title compound (WO2005/042518) as a tangerine solid (5.18 g,99%). Mp: 188° C. (dec). ¹H NMR (400 MHz, CDCl₃) δ: 7.01 (d, J=8.5 Hz,2H), 6.64 (d, J=8.5 Hz, 2H), 3.65 (t, J=5.0 Hz, 2H), 3.61 (s, 2H), 3.45(t, J=5.0 Hz, 2H), 2.35 (t, J=5.0 Hz, 2H), 2.25 (s, 3H), 2.20 (t, J=5.0Hz, 2H). HPLC-MS (ESI+): m/z 467.4 [20%, (2M+H)⁺], 234.2 [100%, (M+H)⁺].

1,1-Dimethylethyl4-chloro-3-(1,1-dimethylethylsulfonamido)phenylcarbamate (SG3-088)

To a solution of SG3-133 (2.80 g, 8.07 mmol) in DCM (30 mL) was addedm-CPBA (65%, 2.143 g, 8.07 mmol) under Argon. The mixture was stirredovernight at room temperature. The reaction mixture was diluted with DCM(200 mL) and washed with saturated NaHCO₃ (2×200 mL) and brine (1×200mL). The organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. The resulting solid was triturated using EtOAc/hexanes to givethe title compound as a light yellow solid (2.59 g, 88%). ¹H NMR (400MHz, CDCl₃) δ: 7.54 (d, J=2.5 Hz, 1H), 7.48 (brd, J=8.9 Hz, 1H), 7.27(d, J=8.9 Hz, 1H), 6.52 (s, 2H), 1.51 (s, 9H), 1.41 (s, 9H). HPLC-MS(ESI+): m/z 749.2 [80%, (M³⁷Cl+M³⁵Cl+H)⁺], 747.2 [100%, (2M³⁵Cl+H)⁺],385.2 [50%, (M³⁵Cl+H)⁺].

tert-Butyl 4-chloro-3-(ethylsulfonamido)phenylcarbamate (SG4-008)

To a solution of SG3-085 (1.00 g, 4.12 mmol) and pyridine (0.997 mL,12.36 mmol) in DCM (4 mL) was added ethanesulfonyl chloride (0.584 ml,6.18 mmol) in DCM (2 mL) at 0° C. The mixture was warmed to roomtemperature and stirred overnight. The reaction mixture was diluted withEtOAc (40 mL) and washed with HCl (1 M aq. solution, 1×20 mL), water(1×20 mL), and brine (1×20 mL). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting residue wastriturated using EtOAc/hexanes to provide the title compound as anoff-white solid (1.289 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d,J=2.5 Hz, 1H), 7.40 (brd, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.72(s, 1H, disappeared on D₂O shake), 6.55 (s, 1H, disappeared on D₂Oshake), 3.14 (q, J=7.4 Hz, 2H), 1.51 (s, 9H), 1.37 (t, J=7.4 Hz, 3H).HPLC-MS (ESI+): m/z 693.2 [60%, (M³⁷Cl+M³⁵Cl+Na)⁺], 691.2 [90%,(2M³⁵Cl+Na)⁺], 359.2 [35%, (M³⁷Cl+Na)⁺], 357.2 [100, (M³⁵Cl+Na)⁺].

N-(5-Amino-2-chlorophenyl)ethanesulfonamide (SG4-009)

A solution of SG4-008 (1.20 g, 3.58 mmol) in TFA/DCM (1:1, 20 mL) wasstirred overnight at room temperature. The mixture was concentratedunder reduced pressure. The pH was adjusted to pH 8-9 by the addition ofNaOH (1 M, aq.) and extracted with EtOAc (2×20 mL). The combined organiclayers were washed with water (1×20 mL) and brine (1×20 mL), dried(Na₂SO₄), and concentrated under reduced pressure. The resulting oil wastriturated using EtOAc/hexanes to provide the title compound as a lightbrown solid (0.776 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ: 7.12 (d, J=8.6Hz, 1H), 7.02 (d, J=2.7 Hz, 1H), 6.67 (s, 1H), 6.40 (dd, J=8.6, 2.7 Hz,1H), 3.13 (q, J=7.4 Hz, 2H), 1.36 (t, J=7.4 Hz, 3H). HPLC-MS (ESI+): m/z237.1 [35%, (M³⁷Cl+H)⁺], 235.1 [100%, (M³⁵Cl+H)⁺].

N-(5-Amino-2-chlorophenyl)-2-methylpropane-1-sulfonamide (SG4-016)

To a solution of SG3-085 (0.242 g, 1.00 mmol) and pyridine (0.242 mL,3.00 mmol) in DCM (0.5 mL) was added isobutanesulfonyl chloride (0.156mL, 1.2 mmol) in DCM (0.5 mL) at 0° C. The mixture was warmed to roomtemperature and stirred overnight. The reaction mixture was diluted withEtOAc (10 mL) and washed with HCl (1 M aq. solution, 1×5 mL), water (1×5mL), and brine (1×5 mL). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting oil was treated withTFA/DCM (1:1, 5 mL) and stirred overnight at room temperature. Themixture was concentrated under reduced pressure. The pH was adjusted topH 8-9 by the addition of NaHCO₃ (saturated, aq.) and extracted withEtOAc (1×5 mL). The organic layer was washed with water (1×5 mL) andbrine (1×5 mL), dried (Na₂SO₄), and concentrated under reduced pressure.The resulting brown oil was triturated using EtOAc/hexanes to providethe title compound as an off-white solid (0.135 g, 52%). ¹H NMR (400MHz, CDCl₃) δ: 7.16 (d, J=8.6 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 6.72 (s,1H), 6.52 (dd, J=8.6, 2.1 Hz, 1H), 2.98 (d, J=6.7 Hz, 2H), 2.27 (dp,J=13.3, 6.7 Hz, 1H), 1.07 (d, J=6.7 Hz, 7H). HPLC-MS (ESI+): m/z 265.2[35%, (M³⁷Cl+H)⁺], 263.2 [100%, (M³⁵Cl+H)⁺].

1-(tert-Butylsulfinyl)-6-nitroindoline (SG4-017)

To a solution of 6-nitroindoline (1.00 g, 6.09 mmol) and pyridine (1.48mL, 18.27 mmol) in DCM (3 mL) was added a solution of t-butylsulfinylchloride (0.751 mL, 6.09 mmol) at 0° C. under Argon. The mixture waswarmed to room temperature and stirred overnight. The reaction mixturewas diluted with EtOAc (50 mL) and washed with HCl (1 M aq. solution,1×50 mL), water (1×50 mL), and brine (1×50 mL). The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. The resultingresidue was triturated using EtOAc/hexanes to provide the title compoundas a dark yellow solid (1.252 g, 77%). Mp: 108° C. (dec). ¹H NMR (400MHz, CDCl₃) δ: 7.82 (dd, J=8.1, 2.1 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H),7.25 (d, J=8.1 Hz, 1H), 4.36 (td, J=10.5, 6.8 Hz, 1H), 3.60 (td, J=10.5,6.8 Hz, 1H), 3.30 (dddd, J=17.3, 10.5, 6.8, 0.8 Hz, 1H), 3.17 (dddd,J=17.3, 10.5, 6.8, 0.8 Hz, 1H), 1.34 (s, 9H). HPLC-MS (ESI+): m/z 559.3[70%, (2M+Na)⁺], 291.2 [100%, (M+H)⁺].

1-(tert-Butylsulfonyl)-6-nitroindoline (SG4-019)

To a solution of SG4-017 (1.122 g, 4.18 mmol) in DCM (20 mL) was addedm-CPBA (65%, 1.03 g, 4.18 mmol) under Argon. The mixture was stirredovernight at room temperature. The reaction mixture was diluted with DCM(100 mL) and washed with saturated NaHCO₃ (1×100 mL) and brine (1×100mL). The organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. The resulting solid was triturated using EtOAc/hexanes to givethe title compound as a yellow solid (1.135 g, 95%). Mp: 113-119° C. ¹HNMR (400 MHz, CDCl₃) δ: 8.14 (d, J=2.1 Hz, 1H), 7.85 (dd, J=8.2, 2.1 Hz,1H), 7.27 (d, J=8.2 Hz, 1H), 4.22 (t, J=8.6 Hz, 2H), 3.22 (t, J=8.6 Hz,2H), 1.51 (s, 9H). HPLC-MS (ESI+): m/z 591.3 [70%, (2M+Na)⁺], 307.2[100%, (M+Na)⁺].

1-(tert-Butylsulfonyl)indolin-6-amine (SG4-020)

To a solution of SG4-019 (1.00 g, 3.517 mmol) in MeOH (25 mL,deoxygenated with Argon gas) was added Pd/C (10%, 0.250 g). A balloon ofhydrogen gas was attached to the flask via a septum cap. The mixture wasstirred at room temperature for 4 h. The reaction mixture was filteredover Celite and the filtrate concentrated under reduced pressure toprovide the title compound as a grey solid (0.833 g, 93%). Mp: 113-116°C. ¹H NMR (400 MHz, CDCl₃) δ: 6.93 (d, J=7.9 Hz, 1H), 6.84 (d, J=2.0 Hz,1H), 6.34 (dd, J=7.9, 2.0 Hz, 1H), 4.08 (t, J=8.4 Hz, 2H), 3.00 (t,J=8.4 Hz, 2H), 1.46 (s, 9H). HPLC-MS (ESI+): m/z 255.1 [100%, (M+H)⁺].

1-(tert-Butylsulfinyl)-7-nitro-1,2,3,4-tetrahydroquinoline (SG4-021)

To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (1.00 g, 5.61 mmol)and pyridine (1.36 mL, 16.84 mmol) in DCM (2.5 mL) was added a solutionof t-butylsulfinyl chloride (0.692 mL, 5.61 mmol) at 0° C. under Argon.The mixture was warmed to room temperature and stirred overnight. Thereaction mixture was diluted with EtOAc (50 mL) and washed with HCl (1 Maq. solution, 1×50 mL), water (1×50 mL), and brine (1×50 mL). Theorganic layer was dried (Na₂SO₄) and concentrated under reducedpressure. The resulting residue was triturated using EtOAc/hexanes toprovide the title compound as an orange solid (0.894 g, 56%). ¹H NMR(400 MHz, CDCl₃) δ: 7.88 (d, J=2.2 Hz, 1H), 7.72 (dd, J=8.3, 2.2 Hz,1H), 7.19 (d, J=8.3 Hz, 1H), 4.19-4.10 (m, 1H), 3.16-3.07 (m, 1H),2.95-2.79 (m, 2H), 2.08-1.99 (m, 1H), 1.82-1.70 (m, 1H), 1.35 (s, 9H).HPLC-MS (ESI+): m/z 587.3 [70%, (2M+Na)⁺], 305.1 [100%, (M+Na)⁺].

1-(tert-Butylsulfonyl)-7-nitro-1,2,3,4-tetrahydroquinoline (SG4-022)

To a solution of SG4-021 (0.873 g, 3.091 mmol) in DCM (15 mL) was addedm-CPBA (65%, 0.762 g, 3.091 mmol) under Argon. The mixture was stirredovernight at room temperature. The reaction mixture was diluted with DCM(100 mL) and washed with saturated NaHCO₃ (1×100 mL) and brine (1×100mL). The organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. The resulting solid was triturated using EtOAc/hexanes to givethe title compound as a yellow solid (0.903 g, 98%). ¹H NMR (400 MHz,CDCl₃) δ: 8.48 (d, J=2.3 Hz, 1H), 7.85 (dd, J=8.4, 2.3 Hz, 1H), 7.23 (d,J=8.4 Hz, 1H), 3.78 (brs, 2H), 2.94 (t, J=6.8 Hz, 2H), 2.14-2.05 (m,2H), 1.55 (s, 9H). HPLC-MS (ESI+): m/z 619.3 [100%, (2M+Na)⁺], 321.2[80%, (M+Na)⁺].

1-(tert-Butylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-amine (SG4-023)

To a solution of SG4-022 (0.750 g, 2.51 mmol) in MeOH (10 mL,deoxygenated with Argon gas) was added Pd/C (10%, 0.200 g). A balloon ofhydrogen gas was attached to the flask via a septum cap. The mixture wasstirred at room temperature for 4 h. The reaction mixture was filteredover Celite and the filtrate concentrated under reduced pressure toprovide the title compound as a light pink solid (0.651 g, 97%). ¹H NMR(400 MHz, CDCl₃) δ: 7.11 (d, J=2.2 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.45(dd, J=8.1, 2.2 Hz, 1H), 5.30 (s, 1H), 3.76-3.68 (m, 2H), 2.73 (t, J=6.8Hz, 2H), 2.01 (quintet, J=6.8 Hz, 2H), 1.46 (s, 9H). HPLC-MS (ESI+): m/z269.2 [100%, (M+H)⁺].

1-(2-Chloro-4-nitrophenyl)-4-methylpiperazine (SG4-029)

3-Chloro-4-fluoronitrobenzene (5.02 g, 28.60 mmol) in a round bottomflask was cooled to 0° C. then treated with 1-methylpiperazine (9.52 mL,85.80 mmol). The solution was warmed to room temperature and stirredovernight. Water (50 mL) was added and the precipitates were filtered,washed with water (3×25 mL), and air-dried to provide the title compound(WO 2011/120026, page 34) as a yellow solid. Mp: 103-105° C. ¹H NMR (400MHz, DMSO-d₆) δ: 8.21 (d, J=2.7 Hz, 1H), 8.13 (dd, J=9.0, 2.7 Hz, 1H),7.27 (d, J=9.0 Hz, 1H), 3.19-3.13 (m, 4H), 2.47-2.45 (m, 4H), 2.22 (s,3H). HPLC-MS (ESI+): m/z 258.2 [35%, (M³⁷Cl+H)⁺], 256.2 [100%,(M³⁵Cl+H)⁺].

3-Chloro-4-(4-methylpiperazin-1-yl)aniline (SG4-030)

To a solution of SG4-029 (2.00 g, 7.82 mmol) in MeOH (32 mL,deoxygenated with Argon gas) was added PtO₂ (18 mg, 0.0782 mmol). Aballoon of hydrogen gas was attached to the flask via a septum cap. Themixture was stirred at room temperature for 5 h. The reaction mixturewas filtered over Celite and the filtrate concentrated under reducedpressure to provide the title compound as a light yellow solid (1.741 g,98%). ¹H NMR (400 MHz, DMSO-d₆) δ: 6.85 (d, J=8.5 Hz, 1H), 6.59 (d,J=2.6 Hz, 1H), 6.45 (dd, J=8.5, 2.6 Hz, 1H), 5.01 (s, 2H, disappeared onD₂O shake), 2.81-2.72 (m, 4H), 2.40 (brs, 4H), 2.18 (s, 3H). HPLC-MS(ESI+): m/z 228.2 [35%, (M³⁷Cl+H)⁺], 226.2 [100%, (M³⁵Cl+H)⁺].

1-Methyl-4-(2-methyl-4-nitrophenyl)piperazine (SG4-035)

2-Fluoro-5-nitrotoluene (1.00 g, 6.45 mmol) and 1-methylpiperazine (2.15mL, 19.34 mmol) placed in a 5 mL microwave vial then stirred and heatedat reflux. Water (10 mL) was added and the precipitates were filtered,washed with water (3×5 mL), and air-dried to provide the title compoundas a yellow solid (1.518 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ: 8.07-8.00(m, 2H), 7.00 (d, J=9.1 Hz, 1H), 3.12-3.04 (m, 4H), 2.63 (brs, 4H), 2.40(s, 3H), 2.36 (s, 3H). HPLC-MS (ESI+): m/z 236.2 [100%, (M+H)⁺].

3-Methyl-4-(4-methylpiperazin-1-yl)aniline (SG4-037)

To a solution of SG4-035 (2.00 g, 8.50 mmol) in MeOH (35 mL,deoxygenated with Argon gas) was added Pd/C (10%, 0.300 g). A balloon ofhydrogen gas was attached to the flask via a septum cap. The mixture wasstirred at room temperature for 17 h. The reaction mixture was filteredover Celite and the filtrate concentrated under reduced pressure toprovide the title compound as a light brown solid (1.708 g, 98%). ¹H NMR(400 MHz, CDCl₃) δ: 6.89 (d, J=8.3 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 6.51(dd, J=8.3, 2.8 Hz, 1H), 3.45 (s, 2H, disappeared on D₂O shake),2.90-2.83 (m, 4H), 2.57 (brs, 4H), 2.36 (s, 3H), 2.23 (s, 3H). HPLC-MS(ESI+): m/z 206.3 [100%, (M+H)⁺].

4-(tert-Butoxycarbonylamino)benzamide (SG3-060)

This was prepared using the reported procedure of Rodríguez et al. (NewBis(2-aminoimidazoline) and Bisguanidine DNA Minor Groove Binders withPotent in Vivo Antitrypanosomal and Antiplasmodial Activity. J. Med.Chem. 2008, 51, 909-923) from Boc-4-Abz-OH (1.00 g), TBTU (1.35 g),aniline (0.384 mL), and triethylamine (2.35 mL) to give the titlecompound as a white solid (1.009 g, 76%). ¹H NMR (400 MHz, DMSO-d₆): δ10.04 (s, 1H, reduced by 50% on D₂O shake), 9.67 (s, 1H, disappeared onD₂O shake), 7.86 (d, J=8.8 Hz, 2H), 7.72 (d, J=7.6 Hz, 2H), 7.55 (d,J=8.8 Hz, 2H), 7.30 (d, J=7.6 Hz, 2H), 7.04 (t, J=7.6 Hz, 1H), 1.46 (s,9H). HPLC-MS (ESI+): m/z 647.3 [100%, (2M+Na)⁺], 313.2 [100%, (M+H)⁺].

4-Aminobenzanilide (SG3-063)

This was prepared using the reported procedure of Rodríguez et al. fromSG3-060 (0.900 g) to give the title compound as a white solid (0.592 g,97%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H, disappeared on D₂Oshake), 7.73 (d, J=8.0, 1.1 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.29 (d,J=8.0 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.58 (d, J=8.7 Hz, 2H), 5.75 (s,2H, disappeared on D₂O shake). HPLC-MS (ESI+): m/z 447.3 [20%,(2M+Na)⁺], 213.2 [100%, (M+H)⁺].

tert-butyl 4-(cyclopropylcarbamoyl)phenylcarbamate (SG3-066)

This was prepared using the reported procedure of Rodríguez et al. fromBoc-4-Abz-OH (1.00 g), TBTU (1.35 g), cyclopropylamine (0.292 mL), andtriethylamine (2.35 mL) to give the title compound as an off-white solid(0.863 g, 74%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.60 (s, 1H, disappeared onD₂O shake), 8.26 (d, J=4.0 Hz, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.46 (d,J=8.7 Hz, 2H), 2.81-2.72 (m, 1H), 1.45 (s, 9H), 0.69-0.59 (m, 2H),0.56-0.47 (m, 2H). HPLC-MS (ESI+): m/z 575.3 [70%, (2M+Na)⁺], 553.3[70%, (2M+H)⁺], 277.3 [100%, (M+H)⁺].

4-Amino-N-cyclopropylbenzamide (SG3-067)

This was prepared using the reported procedure of Rodríguez et al. fromSG3-066 (0.800 g) to give the title compound as a yellow solid (0.500 g,98%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.94 (d, J=3.9 Hz, 1H), 7.52 (d,J=8.7 Hz, 2H), 6.50 (d, J=8.7 Hz, 2H), 5.58 (s, 2H), 2.79-2.71 (m, 1H),0.66-0.59 (m, 2H), 0.55-0.46 (m, 2H). HPLC-MS (ESI+): m/z 375.3 [20%,(2M+Na)⁺], 177.2 [100%, (M+H)⁺].

5,6-Dimethyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (RJ1-004)

Sodium metal (3.20 g, 0.14 mol) was added to dry EtOH (80 mL) underargon before thiourea (5.30 g, 70 mmol) and ethyl methyl-acetoacetate(10.0 g, 70 mmol) were added to the reaction mixture. The reaction washeated to reflux at 90° C. for three hours. The reaction mixture wascooled to ambient temperature and evaporated under reduced pressure. Theproduct obtained was dissolved in cold water and acetic acid was used tobring the pH down to pH 3-4. The resulting solid was filtered, washedwith cold water to provide RJ1-004 as an off-white solid (7.63 g, 70%).m.p.=268° C. (decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (s, 1H),12.08 (s, 1H), 2.07 (s, 3H), 1.73 (s, 3H). LRMS (ESI+) m/z 157.2 (M+H)⁺;(ESI−) m/z 155.0 (M−H)⁻. (Chi, et al., Pyrimidine Research: TheMolecular Rearrangement of2-Ethylmercapto-4,5-dimethyl-6-thiocyanopyrimidine. J. Am. Chem. Soc.1936, 58, 769-771.)

5,6-Dimethylpyrimidine-2,4(1H,3H)-dione (RJ1-006) (WO2013/123401)

A mixture of 1a (7.18 g, 46 mmol), chloroacetic acid (50.09 g, 0.530mol), and water (21.5 mL, 1.20 mol) was heated to reflux under argon at100° C. for 23 hours. After cooling to ambient temperature, the reactionmixture was quenched with water (250 mL). The precipitate that formedwas filtered and washed with water to provide RJ1-006 as a white solid(4.68 g, 73%). m.p.=288° C. (decomposed). ¹H NMR (400 MHz, DMSO-d₆) δ10.89 (s, 1H), 10.59 (s, 1H), 2.00 (s, 3H), 1.68 (s, 3H). LRMS (ESI+)m/z 141.2 (M+H)⁺; (ESI−) m/z 139.1 (M−H)⁻.

2,4-Dichloro-5,6-dimethylpyrimidine (RJ1-008) (WO2013/123401)

A mixture of RJ1-006 (4.00 g, 28.5 mmol), phosphorus(V) oxychloride (60mL, 0.642 mol), and dimethylformamide (0.08 mL, 1.03 mmol) was heated toreflux at 110° C. for 23 hours. The reaction mixture was then cooled toambient temperature and evaporated. Toluene (80 mL) was added to theresidue and the resulting mixture was concentrated. Cold water with ice(160 mL) was added to the residue, and the mixture was extracted withchloroform (3×60 mL). The combined organic layers were washed with brine(2×150 mL), dried over sodium sulfate, filtered, and concentrated toprovide RJ1-008 as a pale yellow solid (4.37 g, 87%). m.p.=68-70° C. ¹HNMR (400 MHz, CDCl₃) δ 2.55 (s, 3H), 2.34 (s, 3H). LRMS (ESI+) m/z 177.1(MCl³⁵Cl³⁵+H)⁺, 179.0 (MCl³⁵Cl³⁷+H)⁺, 181.0 (MCl³⁷Cl³⁷+H)⁺.

N-Cyclopropyl-3-nitrobenzenesulfonamide (RJ1-016)

3-Nitrobenzenesulfonyl chloride (1.0 g, 4.5 mmol) was added to a roundbottom flask followed by dry THF (10 mL) and cyclopropylamine (0.93 mL,13.5 mmol), both under argon, at ambient temperature with stirring.After thirty minutes, the pH of the reaction mixture was brought down topH 1 using 4M HCl, and the mixture was evaporated under reducedpressure. The off-white solid was then triturated with EtOAc and hexanesand filtered. The remaining oily residue was diluted with water (10 mL)and extracted with EtOAc (2×10 mL). The organic layer was separated,dried over sodium sulfate, filtered and evaporated, producing a lightpink solid. The two crops were determined to be the same by NMR andtogether give RJ1-016 (0.98 g, 89%). m.p.=123-124° C. ¹H NMR (400 MHz,DMSO-d₆) δ 8.16 (dt, J=2.5, 1.4 Hz, 2H), 7.91 (s, 1H), 7.86 (dd, J=7.8,1.1 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 1.86-1.75 (m, 1H), 0.13 (dd, J=6.9,4.7 Hz, 2H), 0.03 (dd, J=6.6, 3.3 Hz, 2H). LRMS (ESI+) m/z 243.1 (M+H)⁺;(ESI−) m/z 241.1 (M−H)⁻.

N-(3-Nitrophenyl)cyclopropanesulfonamide (RJ1-020)

3-Nitroaniline (0.100 g, 0.724 mmol) was added to a microwave vial whichwas then sealed. Dry DCM (3.5 mL), anhydrous pyridine (0.175 mL), andcyclopropanesulfonyl chloride (0.11 mL) were all then added to thesealed tube under argon. The tube was stirred at room temperature foreighteen hours before being concentrated, re-dissolved in DCM, separatedvia flash chromatography eluting with hexanes/EtOAc to provide RJ1-020as a yellow-white solid (0.154 g, 88%). m.p.=134-135° C. ¹H NMR (400MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.10-7.98 (m, 1H), 7.92 (dt, J=6.7, 2.3Hz, 1H), 7.67-7.55 (m, 2H), 2.80-2.68 (m, 1H), 0.95 (d, J=6.4 Hz, 4H).LRMS (ESI+) m/z 243.1 (M+H)⁺; (ESI−) m/z 241.1 (M−H)⁻.

3-Amino-N-cyclopropylbenzenesulfonamide (RJ1-042)

To a two-neck round bottom flask was added Pd/C (0.250 g), followed bydeoxygenated hydrazine (0.533 mL, 11.1 mmol), and RJ1-016 (0.900 g, 3.72mmol) dissolved in deoxygenated EtOH (25 mL). The flask was heated toreflux under argon in a hot oil bath at 90° C. with stirring for fourhours. After formation of the desired product was confirmed by TLC andLC/MS, the flask was removed from the oil bath and allowed to cool toambient temperature. The reaction mixture was filtered through a bed ofCelite wetted with MeOH using deoxygenated MeOH (3×25 mL, 100 mL). Thefiltrate was then evaporated under reduced pressure after the Celite andPd/C had been quenched with water. After evaporation, a white solidprecipitated once the flask cooled to ambient temperature, which wasidentified as the product RJ1-042 (0.757 g, 96%). m.p.=115-118° C. ¹HNMR (400 MHz, DMSO-d₆) δ 7.73 (d, J=2.1 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H),7.00 (t, J=2.0 Hz, 1H), 6.91-6.86 (m, 1H), 6.75 (ddd, J=8.0, 2.2, 0.8Hz, 1H), 5.58 (s, 1H), 2.06 (td, J=6.7, 3.2 Hz, 1H), 0.46 (qd, J=7.7,3.6 Hz, 2H), 0.42-0.36 (m, 2H). LRMS (ESI+) m/z 213.2 (M+H)⁺; HRMS(ESI+) m/z calculated for C₉H₁₂N₂O₂S (M+Na)⁺ 235.05117, found 235.05075,(M+H)⁺ 213.06922, found 213.06890.

N-(3-Aminophenyl)cyclopropanesulfonamide (RJ1-025)

To a three-neck round bottom flask was added Pd/C (0.500 g), followed bydeoxygenated hydrazine (2.4 mL, 11.1 mmol), and RJ1-020 (4.000 g, 16.5mmol) dissolved in deoxygenated EtOH (120 mL). The mixture was allowedto react following the same procedure as RJ1-042, with the exceptionthat after 25 hours, hydrazine hydrate (1.2 mL, 1.5 equiv.),deoxygenated EtOH (5 mL) and Pd/C (0.250 g) were added to the reactionmixture under argon. The mixture was allowed to react for another 11hours and worked up in the same manner as RJ1-042 to give a viscous,dark green/yellow material as the final product RJ1-025 (3.482 g, 99%).¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 6.89 (t, J=7.9 Hz, 1H), 6.47(s, 1H), 6.36 (d, J=7.9 Hz, 1H), 6.26 (d, J=9.1 Hz, 1H), 5.13 (s, 2H),2.58-2.44 (m, 1H), 0.90 (t, J=6.2 Hz, 4H). LRMS (ESI+) m/z 213.1 (M+H)⁺;(ESI−) m/z 211.2 (M−H)⁻; HRMS (ESI+) m/z calculated for C₉H₁₂N₂O₂S(M+H)⁺ 213.06922, found 213.07037.

N-(3-Aminophenyl)-1,1-dimethylethylcarboxamide (MA2-040-1)

This was prepared from MA2-036-1 (1.100 g), (NH₄)₂CO₃ (0.946 g), Pd/C(0.532 g), and EtOH (12 mL) using the general method c (reaction time,18 h) to provide the title compound as a light yellow solid (0.750 g,99%). Mp: 251° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.86 (s, 1H), 6.93(t, J=2.0 Hz, 1H), 6.88 (t, J=8.0 Hz, 1H), 6.71 (d, with unresolved finecoupling, J=8.0 Hz, 1H) 1H), 6.25 (d, with unresolved fine coupling,J=8.0 Hz, 1H), 4.99 (s, 2H, disappeared on D₂O shake), 1.19 (s, 9H).HPLC-MS (ESI+): m/z 193.2 [100%, (M+H)⁺].

N-(3-Aminophenyl)-1-methylethylcarboxamide (MA2-040-2)

This was prepared from MA2-036-2 (1.62 g), (NH₄)₂CO₃ (1.47 g), Pd/C(10%, 0.825 g), and EtOH (12 mL) using the general method c (reactiontime, 18 h) to provide the title compound as a white solid (1.10 g,81%). Mp: 115-117° C. ¹H NMR (400 MHz, DMSO-d) δ: 9.49 (s, 1H), 6.92 (s,1H), 6.88 (t, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.22 (d, withunresolved fine coupling, J=8.0, 1H), 5.01 (s, 2H, disappeared on D₂Oshake), 2.59-2.51 (m, 1H), 1.06 (d, J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z179.2 [100%, (M+H)⁺].

N-(3-Aminophenyl)cyclopropanecarboxamide (MA2-040-3)

This was prepared from MA2-036-3 (1.46 g), (NH₄)₂C₃ (1.34 g), Pd/C (10%,0.757 g), and EtOH (12 mL) using the general method c (reaction time, 18h) to provide the title compound as a white solid (1.10 g, 81%). Mp:126-131° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H, 70% reduced on D₂Oshake), 6.92-6.88 (m, 1H), 6.86 (t, J=8.0 Hz, 1H), 6.67 (d, J=8.0 Hz,1H), 6.24 (d, with unresolved fine coupling, J=8.0 Hz, 1H), 5.02 (s, 2H,disappeared on D₂O shake), 1.78-1.71 (m, 1H), 0.78-0.72 (m, 4H). HPLC-MS(ESI+): m/z 177.2 [100%, (M+H)⁻].

N-(3-Aminophenyl)propane-2-sulfonamide (MA3-004)

This was prepared from MA2-086 (2.2 g), (NH₄)₂CO₃ (7 g), Pd/C (10%,0.956 g), and EtOH (20 mL) using the general method c (reaction time, 18h) to provide the title compound as a white solid (1.56 g, 81%). Mp:297° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.41 (s, 1H, disappeared onD₂O shake), 6.89 (t, J=8.0 Hz, 1H), 6.47 (t, J=2.1 Hz, 1H), 6.35 (d,with unresolved fine coupling, J=8.0 Hz, 1H), 6.25 (d, with unresolvedfine coupling, J=8.0 Hz, 1H), 5.15 (s, 2H, disappeared on D₂O shake),3.18 (septet d, J=6.8 Hz, 6H, J=6.8 Hz, 1H), 1.22 (d, J=6.8 Hz, 6H).HPLC-MS (ESI+): m/z 451.2 [10%, (2M+Na)⁺], 215.1 [100%, (M+H)⁺].

N-(3-Aminophenyl)benzenesulfonamide (MA3-092)

This was prepared from MA3-086 (2.17 g, 1 equiv.) and hydrazinemonohydrate (1.17 mL, 3 equiv.) using the general method b. The titlecompound MA3-092 was obtained as a yellow oil which solidified after 1 h(1.83 g, 95%). Mp: 87-90° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.95 (s, 1H,disappeared on D₂O shake), 7.76 (s, 1H), 7.74 (d, J=1.4 Hz, 1H),7.63-7.49 (m, 3H), 6.79 (t, J=8.0 Hz, 1H), 6.35 (t, J=1.9 Hz, 1H), 6.22(d, J=8.0 Hz, 1H), 6.18 (d, J=8.1 Hz, 1H), 5.10 (s, 2H, disappeared onD₂O shake). HPLC-MS (ESI+): m/z 249.2 [100%, (M+H)⁺].

1-Isopropyl-3-(3-nitrophenyl)urea (MA2-054-2)

A solution of 3-nitrophenylisocyanate (1.15 g) in dry ether (10 mL) wascooled to 0° C. (ice-water bath) and while keeping the reaction underargon, isopropylamine (630 μL, 1.1 equiv.) was added via a Hamiltonsyringe. The reaction mixture was allowed to warm to room temperatureand stirred for 4 h. The precipitate was filtered and washed with hexane(15 mL×3) and dried to provide MA2-054-2 as white powder (1.43 g, 80%).Mp: 162-163° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.84 (s, 1H, disappeared onD₂O shake), 8.51 (t, J=2.2 Hz, 1H), 7.73 (ddd, J=8.1, 2.3, 0.9 Hz, 1H),7.59 (ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 6.20 (d,J=7.5 Hz, 1H, 55% reduced on D₂O shake), 3.79-3.74 (m, 1H), 1.11 (d,J=6.5 Hz, 6H). HPLC-MS (ESI+): m/z 469.1 [35%, (2M+Na)⁺], 447.2 [95%,(2M+H)⁺], 224.2 [100%, (M+H)⁺].

1-(3-Aminophenyl)-3-isopropylurea (MA2-056-2)

This was prepared from MA2-054-2 (1.41 g), (NH₄)CO₃ (1.34 g), Pd/C(0.757 g), and EtOH (15 mL) using the general method c (reaction time, 3h) and purified via column chromatography (SiO₂) eluting with DCM/EtOAc(10:0 to 10:1 v/v) to provide the title compound MA2-056-2 as a yellowsolid (0.661 g, 53%). Mp: 173-175° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.95(s, 1H), 6.81 (t, J=7.9 Hz, 1H), 6.67 (t, J=2.0 Hz, 1H), 6.46 (d, withunresolved fine coupling, J=7.5 Hz, 1H), 6.09 (ddd, J=7.9, 2.0, 0.9 Hz,1H), 5.86 (d, J=7.5 Hz, 1H), 4.92 (s, 2H), 3.78-3.62 (m, 1H), 1.07 (d,J=6.5 Hz, 6H).

N-(3-Nitrophenyl)benzenesulfonamide (MA3-086)

This was prepared from m-nitroaniline (1.38 g), pyridine (4.02 mL, 5eq.) and benzenesulfonyl chloride (4.4 g, 2.5 equiv.) using the generalmethod a1 (reaction time, 16 h). The title compound MA3-086 was obtainedas a yellow solid (2.21 g, 79%). Mp: 131° C. (dec). ¹H NMR (400 MHz,DMSO-d₆) δ: 10.96 (s, 1H,), 7.94-7.92 (m, 1H), 7.88 (dd, J=7.5, 1.9 Hz,1H), 7.82-7.79 (m, 2H), 7.64 (t, J=7.3 Hz, 1H), 7.61-7.57 (m, 2H),7.55-7.51 (m, 2H). HPLC-MS (ESI+): m/z 578.9 [40%, (2M+Na)⁺], 299.2[100%, (M+Na)⁺].

tert-Butyl (4-chloro-3-(phenylsulfonamido)phenyl)carbamate (MA3-093)

This was prepared in the same manner as SG3-084 using the reportedprocedure of Sloss et al. from SG3-085 (1.46 g, 1 equiv.) andbenzenesulfonyl chloride (0.983 mL, 1.1 equiv.). The resulting residuewas purified via column chromatography (SiO₂) eluting with hexanes/EtOAc(10:0 to 1:1 v/v) to give the title compound as a white solid (1.64 g,72%). Mp: 119-121° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.90 (s, 1H), 9.57(s, 1H), 7.73 (brs, 1H), 7.72 (t, J=1.7 Hz, 1H), 7.64 (t, J=7.4 Hz, 1H),7.56 (brs, 1H), 7.54-7.51 (m, 3H), 7.27 (dd, J=8.8, 2.4 Hz, 1H), 7.23(d, J=8.8 Hz, 1H), 1.46 (s, 9H). HPLC-MS (ESI+): m/z 787.1 [60%,(2M+Na)⁺], 400.3 [60%, (M+NH₄)⁺].

N-(2-Fluoro-5-nitrophenyl)-2-methylpropane-2-sulfinamide (MA3-094)

This was prepared from 2-fluoro-5-nitroaniline (0.781 mg, 1 equiv.) andtert-butylsulfonyl chloride (925 μL, 1.5 equiv.) using the sameprocedure as for the synthesis of SG3-115. The title compound wasobtained as a brown solid (0.671 g, 52%). Mp: 86-89° C. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.31 (s, 1H), 8.13 (dd, J=7.1, 2.8 Hz, 1H), 7.99-7.90 (m,1H), 7.53 (dd, J=10.3, 9.1 Hz, 1H), 1.27 (s, 9H). HPLC-MS (ESI+): m/z283.1 [60%, (M+Na)⁺], 261.1 [100%, (M+H)⁺].

N-(2-Fluoro-5-nitrophenyl)-2-methylpropane-2-sulfonamide (MA3-098)

This was prepared from MA3-094 (0.632 g, 1 equiv.) and mCPBA (0.658 g,1.1 equiv.) using the same procedure as for the synthesis of SG3-123.The title compound was obtained as a yellow solid (0.637 g, 95%). Mp:220° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.20 (s, 1H), 8.38 (dd,J=6.9, 2.8 Hz, 1H), 8.09 (ddd, J=9.1, 4.1, 2.9 Hz, 1H), 7.58 (t, J=9.1Hz, 1H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z 575.3 [10%, (2M+Na)⁺], 299.3[65%, (M+Na)⁺], 294.2 [55%, (M+NH₄)⁺].

N-(5-Amino-2-chlorophenyl)benzenesulfonamide (MA4-002)

This was prepared from MA3-093 (1.57 g, 1 equiv.) and TFA:DCM (1:1, 15mL) using the same procedure as for the synthesis of MA1-098 (reactiontime, 2 h). The title compound was obtained as a yellow solid (1.1 g,95%). Mp: 155° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.61 (s, 1H,disappeared on D₂O shake), 7.73 (s, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.63(t, J=7.4 Hz, 1H), 7.54 (t, J=7.4 Hz, 2H), 6.93 (d, J=8.6 Hz, 1H), 6.55(d, J=2.6 Hz, 1H), 6.35 (dd, J=8.6, 2.6 Hz, 1H), 5.35 (s, 2H,disappeared on D₂O shake). HPLC-MS (ESI+): m/z 589.1 [15%,(2M³⁷Cl³Cl+Na)⁺], 587.1 [30%, (2M³⁵Cl³⁵Cl+Na)⁺], 285.1 [40%,(M³⁷Cl+H)⁺], 283.1 [100%, (M³⁵Cl+H)⁺].

N-(5-Amino-2-fluorophenyl)-2-methylpropane-2-sulfonamide (MA4-024)

This was prepared from MA3-098 (0.600 g, 1 equiv.) and hydrazinemonohydrate (698 mg, 6 equiv.) and Pd/C (10%, 0.494 g, 0.2 equiv.) usingmethod b (reaction time, 2 h). The title compound was obtained as a pinksolid (0.522 g, 91%). Mp: 146° C. (dec). ¹H NMR (400 MHz, DMSO-d₆) δ:8.91 (brs, 1H, disappeared on D₂O shake), 6.85 (dd, J=10.4, 8.7 Hz, 1H),6.71 (dd, J=7.0, 2.8 Hz, 1H), 6.31 (ddd, J=8.7, 3.9, 2.8 Hz, 1H), 5.02(s, 2H, disappeared on D₂O shake), 1.27 (s, 9H). HPLC-MS (ESI+): m/z493.2 [50%, (2M+H)⁺], 247.2 [100%, (M+H)⁺].

N-Cyclobutyl-2-methyl-5-nitrobenzenesulfonamide (MA4-076)

This was prepared from 2-methyl-5-nitrobenzenesulfonyl chloride (1.18 g,1 equiv.) and cyclobutylamine (0.391 g, 1.1 equiv.) using the generalmethod a1, with pyridine (0.593 g, 1.5 eq.). The crude mixture waspurified via column chromatography (SiO₂) eluting with hexanes/EtOAc(1:9 to 1:1 v/v) to give the title compound as a white solid (0.924 g,68%). Mp: 103-105° C. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.53 (d, J=2.5 Hz,1H), 8.46 (d, J=8.5 Hz, 1H, disappeared on D₂O shake), 8.36 (dd, J=8.5,2.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 3.71-3.58 (m, 1H), 2.70 (s, 3H),1.96-1.78 (m, 4H), 1.56-1.39 (m, 2H). HPLC-MS (ESI+): m/z 563.1 [25%,(2M+Na)⁺], 293.1 [100%, (M+Na)⁺], 271.2 [10%, (M+H)⁺].

5-Amino-N-cyclobutyl-2-methylbenzenesulfonamide (MA4-080)

This was prepared by reduction of MA4-076 according to the generalmethod b. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.74 (d, J=8.8 Hz, 1H,disappeared on D₂O shake), 7.08 (d, J=2.5 Hz, 1H), 6.96 (d, J=8.2 Hz,1H), 6.63 (dd, J=8.2, 2.5 Hz, 1H), 5.29 (s, 2H, disappeared on D₂Oshake), 3.50 (sextet, J=8.2 Hz, 1H), 2.36 (s, 3H), 1.93-1.74 (m, 4H),1.55-1.36 (m, 2H). HPLC-MS (ESI+): m/z 481.3 [50%, (2M+H)⁺], 241.2[100%, (M+H)⁺].

N-(3,5-Dinitrophenyl)acetamide (MA4-041)

This was prepared by refluxing 3,5-dinitroaniline (1 g, 1 equiv.),glacial acetic acid (2.62 g, 8 equiv.) and acetic anhydride (1.08 g,1.94 equiv.) using the literature procedure. The title compound MA4-041was obtained as white solid (1.15 g, 94%). ¹H NMR (400 MHz, DMSO-d₆) δ:10.87 (s, 1H, disappeared on D₂O shake), 8.83 (d, J=2.1 Hz, 2H), 8.49(t, J=2.1 Hz, 1H), 2.15 (s, 3H). HPLC-MS (ESI+): m/z 248.2 [100%,(M+Na)⁺].

N-(3,5-Diaminophenyl)acetamide (MA4-042)

This was prepared by refluxing MA4-041 (1 g, 1 equiv.), hydrazinemonohydrate (1.7 g, 8 equiv.) and Pd/C (10%, 0.20 g, 0.04 equiv.) usinga reported procedure. The title compound was obtained as a brown oil(0.610 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.30 (s, 1H, 40% reduced onD₂O shake), 6.09 (s, 2H), 5.51 (s, 1H), 4.67 (s, 4H, disappeared on D₂Oshake), 1.94 (s, 3H). HPLC-MS (ESI+): m/z 166.2 [100%, (M+H)⁺].

N-[3,5-Bis(cyclopropanesulfonamido)phenyl]acetamide (MA4-043)

This was prepared by stirring MA4-042 (0.165 g, 1 equiv.),cyclopropanesulfonyl chloride (0.422 g, 3 equiv.) and pyridine (0.475 g)in DCM (4 mL) using a reported procedure (0° C. to rt, reaction time 2h). After work-up the title compound MA4-043 was obtained as a whitesolid (0.358 g, 96%). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.02 (s, 1H,disappeared on D₂O shake), 9.78 (s, 2H, disappeared on D₂O shake), 7.29(s, 2H), 6.87 (s, 1H), 2.59-2.52 (m, 2H), 2.01 (s, 3H), 1.00-0.91 (m,8H). HPLC-MS (ESI+): m/z 747.2 [100%, (2M+H)⁺], 374.2 [65%, (M+H)⁺].

N,N′-(5-Amino-1,3-phenylene)dicyclopropanesulfonamide (MA4-044)

This was prepared by heating MA4-043 (0.033 g, 1 equiv.), in a mixtureof HCl (20% aq., 0.435 mL, 2.5 equiv.) and EtOH (0.5 mL) using areported procedure (sealed tube, 60° C., 4 h). The title compoundMA4-044 was obtained as a light green solid (0.023 g, 74%). ¹H NMR (400MHz, DMSO-d₆) δ: 9.43 (s, 2H, disappeared on D₂O shake), 6.38 (t, J=1.9Hz, 1H), 6.21 (d, J=1.9 Hz, 2H), 5.27 (s, 2H, disappeared on D₂O shake),2.60-2.45 (m, 2H), 0.98-0.88 (m, 8H). HPLC-MS (ESI+): m/z 663.1 [45%,(2M+H)⁺], 332.2 [100%, (M+H)⁺].

N-(3-Nitrophenyl)pivalamide (MA2-036-1)

This was prepared by stirring 3-nitroaniline (1.38 g), pivaloyl chloride(1.30 g, 1.1 equiv.) and triethylamine (1.5 mL, 1.1 equiv.) in DCM usinga reported procedure (Ueda, et al., Copper-catalyzed synthesis ofbenzoxazoles via a regioselective C—H functionalization/C—O bondformation under an air atmosphere. J Org Chem 2009, 74, 4272-7). Thetitle compound was obtained as a white solid (1.67 g, 75%). Mp: 110-113°C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.68 (s, 1H, disappeared on D₂O shake),8.67 (t, J=2.1 Hz, 1H), 8.09 (d, with unresolved fine coupling, J=8.2Hz, 1H), 7.89 (d, with unresolved fine coupling, J=8.2 Hz, 1H), 7.58 (t,J=8.2 Hz, 1H), 1.24 (s, 9H). HPLC-MS (ESI+): m/z 223.2 [10%, (M+H)⁺].

N-(3-Nitrophenyl)isobutyramide (MA2-036-2)

This was prepared by stirring 3-nitroaniline (1.38 g), pivaloyl chloride(1.17 g, 1.1 equiv.) and triethylamine (1.5 mL, 1.1 equiv.) in DCM usinga reported procedure (Ueda et al.). The title compound was obtained as awhite solid (1.63 g, 80%). Mp: 100-101° C. ¹H NMR (400 MHz, DMSO-d₆): δ10.33 (s, 1H, disappeared on D₂O shake), 8.66 (t, J=2.2 Hz, 1H), 7.93(ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.88 (ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.59(t, J=8.2 Hz, 1H), 2.60 (septet, J=6.8 Hz, 1H), 1.12 (d, J=6.8 Hz, 6H).HPLC-MS (ESI+): m/z 209.2 [20%, (M+H)⁺], HPLC-MS (ESI−): m/z 207.1 [30%,(M−H)⁺].

N-(3-Nitrophenyl)cyclopropanecarboxamide (MA2-036-3)

This was prepared by stirring 3-nitroaniline (1.38 g), pivaloyl chloride(1.15 g, 1.1 equiv.) and triethylamine (1.5 mL, 1.1 equiv.) in DCM usinga reported procedure (Ueda et al.). The title compound was obtained as agray solid (1.47 g, 71%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H,disappeared on D₂O shake), 8.64 (t, J=2.2 Hz, 1H), 7.93-7.85 (m, 2H),7.59 (t, J=8.2 Hz, 1H), 1.79 (quintet, J=6.2 Hz, 1H), 0.85 (d, J=6.2 Hz,4H). HPLC-MS (ESI+): m/z 207.1 [10%, (M+H)⁺].

N-(3-Aminophenyl)-2-methylpropane-2-sulfonamide (MA3-010)

This was prepared from MA3-009 (0.54 g, 1 equiv.), hydrazine monohydrate(0.314 mL, 3 equiv.) using the general method b. The title compoundMA3-010 was obtained as a gray solid (0.362 g, 76%). Mp: 194-195° C. ¹HNMR (400 MHz, DMSO-d₆) δ: 9.28 (s, 1H), 6.86 (t, J=8.0 Hz, 1H), 6.53 (t,J=2.1 Hz, 1H), 6.43 (ddd, J=8.0, 2.1, 0.8 Hz, 1H), 6.23 (ddd, J=8.0,2.1, 0.8 Hz, 1H), 5.10 (s, 2H), 1.25 (s, 9H). HPLC-MS (ESI+): m/z 479.2[10%, (2M+Na)⁺], 229.1 [100%, (M+H)⁺].

N-(3-Nitrophenyl)propane-2-sulfinamide (MA2-044)

This was prepared from m-nitroaniline (0.692 mL, 1 equiv.),tert-butylsulfinyl chloride (0.682 mL, 1.1 equiv.) and pyridine (682 mL,1.1 equiv.) using a reported procedure (WO2006/033631; Sun, et al.,tert-Butylsulfonyl (Bus), a New Protecting Group for Amines. J Org Chem1997, 62, 8604-8608). The title compound was obtained as yellow oil(0.860 g, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.61 (s, 1H), 7.91 (t,J=1.9 Hz, 1H), 7.77 (dt, J=7.4, 1.9 Hz, 1H), 7.59-7.49 (m, 2H), 1.26 (s,9H). HPLC-MS (ESI+): m/z 485.2 [100%, (2M+H)⁺], 243.1 [65%, (M+H)⁺].

N-(3-Nitrophenyl)-2-methylpropane-2-sulfonamide (MA3-009)

This was prepared from MA2-044 (0.745 g, 1 equiv.) and mCPBA (0.795 g,1.5 equiv.) by the same procedure (WO2006/033631; Sun, et al.) used toprepare SG3-123. The title compound was obtained as a yellow solid(0.552 g, 70%). ¹H NMR (400 MHz, DMSO-d) 6:10.26 (s, 1H), 8.13 (t, J=2.2Hz, 1H), 7.91-7.87 (m, 1H), 7.73-7.66 (m, 1H), 7.58 (t, J=8.2 Hz, 1H),1.30 (s, 9H). HPLC-MS (ESI−): m/z 257.1 [100%, (M−H)⁻].

1-Methyl-N-(3-nitrophenyl)cyclopropane-1-sulfonamide (MA4-086)

This was prepared by stirring m-nitroaniline (0.414 g, 1 equiv.),1-methylcyclopropanesulfonyl chloride (0.464 g, 2.5 equiv.) and pyridine(0.982 g, 3 equiv.) in DCM (15 mL) using general method a (reactiontime, 16 h). The title compound MA4-086 was obtained as a yellow solid(2.21 g, 79%). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.42 (s, 1H, disappeared onD₂O shake), 8.07 (t, J=2.1 Hz, 1H), 7.94 (ddd, J=8.0, 2.1, 1.3 Hz, 1H),7.66 (ddd, J=8.0, 2.0, 1.3 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 1.18-1.11(m, 2H), 0.86-0.78 (m, 2H). HPLC-MS (ESI+): m/z 535.1 [20%, (2M+Na)⁺],279.1 [100%, (M+Na)⁺], 257.1 [25%, (M+H)⁺].

tert-Butyl(4-chloro-3-((1-methylcyclopropane)-1-sulfonamido)phenyl)-carbamate(MA5-004)

This was prepared by stirring SG3-085 (0.30 g, 1 equiv.),1-methylcyclopropane sulfonyl chloride (0.287 g, 1.5 equiv.), pyridine(0.299 mL, 3 equiv.) in DCM using method a (0° C. to rt, 5 h). The titlecompound MA5-004 was obtained as an orange solid (0.380 g, 94%). ¹H NMR(400 MHz, DMSO-d₆) δ: 9.58 (s, 1H, disappeared on D₂O shake), 9.39 (s,1H, disappeared on D₂O shake), 7.69 (s, 1H), 7.38-7.28 (m, 2H) 1.47(brs, 12H), 1.10-1.06 (m, 2H), 0.81-0.77 (m, 2H). HPLC-MS (ESI−): m/z361.2 [40%, (M³⁷Cl—H)⁻], 359.1 [100%, (M³⁵Cl—H)⁻].

1-Methyl-N-(3-aminophenyl)cyclopropane-1-sulfonamide (MA4-096)

This was prepared by refluxing MA4-086 (0.482 g, 1 equiv.),hydrazine-monohydrate (0.565 g, 6 equiv.) and Pd/C (0.200 g) in EtOH (4mL) using method b (reaction time, 16 h). The title compound MA4-096 wasobtained as a yellow solid (0.402 g, 94%). ¹H NMR (400 MHz, DMSO-d₆) δ:6.88 (t, J=8.0 Hz, 1H), 6.49 (t, J=2.1 Hz, 1H), 6.37 (ddd, J=8.0, 2.1,0.9 Hz, 1H), 6.25 (ddd, J=8.0, 2.1, 0.9 Hz, 1H), 5.12 (s, 2H,disappeared on D₂O shake), 1.37 (s, 3H), 1.11-1.07 (m, 2H), 0.72-0.68(m, 2H). HPLC-MS (ESI+): m/z 475.2 [10%, (2M+H)⁺], 227.2 [100%, (M+H)⁺].

N-(5-Amino-2-chlorophenyl)-1-methylcyclopropane-1-sulfonamide (MA5-010)

This was prepared from MA3-093 (1.57 g, 1 equiv.) and TFA:DCM (1:1, 15mL) by the same procedure used to prepare MA1-098 (reaction time, 2 h).The title compound was obtained as a yellow solid (1.1 g, 95%). ¹H NMR(400 MHz, DMSO-d₆) δ: 9.07 (s, 1H, disappeared on D₂O shake), 7.04 (d,J=8.5 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 6.40 (dd,J=8.6, 2.6 Hz, 1H), 5.35 (s, 2H, disappeared on D₂O shake), 1.44 (s,3H), 1.10-1.06 (m, 2H), 0.79-0.75 (m, 2H). HPLC-MS (ESI+): m/z 263.1[40%, (M³⁷Cl+H)⁺], 261.1 [100%, (M³⁵Cl+H)⁺].

Example 2: Generally Synthesis

Method x:

A mixture of 4-anilino-pyrimidine intermediate 3 (50 mg, 1.0 equiv.),the corresponding aniline B-ring aniline (1.0 equiv.), 2 drops of 4 MHCl, and EtOH (1 mL) was heated in a microwave reactor at 160° C. for 15minutes. The reaction mixture was diluted with EtOAc (20 mL) and washedwith saturated NaHCO₃ (20 mL). The aqueous layer was then re-extractedwith EtOAc (20 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. Unless otherwise mentioned, allproducts were purified via column chromatography using DCM/MeOH (0-10%).

Method y:

A mixture of 4-anilino-pyrimidine intermediate 3 (50 mg, 1.0 equiv.),the corresponding aniline B-ring aniline (1.0 equiv.), 2 drops of 4 MHCl, and EtOH (1 mL) was heated in a microwave reactor at 100° C. for 1h. Sodium bicarbonate (ca. 100 mg) was added to the mixture, stirred for30 min at room temperature, and concentrated under reduced pressure.Unless otherwise mentioned, all products were purified via columnchromatography using DCM/MeOH (0-10%).

Specific compounds

5-Chloro-N⁴-(4-chloro-3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG1-180)

This was prepared from SG1-168 (50 mg) and 4-(4-methylpiperazino)aniline(31 mg) using the general method x. The crude reaction mixture wastriturated using EtOAc/hexanes to give the title compound as a lightbrown solid (50 mg, 66%). Mp: 232° C. (dec). HPLC: 96% [t_(R)=5.8 min,40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆):δ 9.10 (s, 1H, disappeared on D₂O shake), 8.82 (s, 1H, disappeared onD₂O shake), 8.09 (s, 1H), 7.46-7.26 (m, 5H), 6.78 (d, J=8.6 Hz, 2H),3.70 (s, 3H), 3.06-2.98 (m, 4H), 2.46-2.41 (m, 4H), 2.21 (s, 3H).HPLC-MS (ESI+): m/z 461.2 [60%, (M³⁵Cl³⁷Cl+H)⁺], 459.2 (100%,M³⁵Cl³⁵Cl+H)⁺], 231.1 [60%, (M³⁵Cl³⁷Cl+2H)²⁺], 230.1 [90%,M³⁵Cl³⁵Cl+2H)²⁺]. LC-MS (ESI+): 461.1 [70%, (M³⁵Cl³⁷Cl+H)⁺], 459.1[100%, (M³⁵Cl³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₂H₂₄Cl₂N₆₀ (M+H)⁺459.1461, found 459.1458.

5-Methyl-N⁴-(4-chloro-3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG1-183)

This was prepared from SG1-173-01 (50 mg) and4-(4-methylpiperazino)aniline (34 mg) using the general method x. Thecrude reaction mixture was triturated using EtOAc/hexanes to give thetitle compound as a light brown solid (49 mg, 64%), mp 257° C. (dec).HPLC: 98% [t_(R)=8.9 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H, disappeared on D₂O shake),8.28 (s, 1H, disappeared on D₂O shake), 7.85 (s, 1H), 7.50-7.39 (m, 4H),7.26 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.7 Hz, 2H), 3.71 (s, 3H), 3.04-2.96(m, 4H), 2.45-2.40 (m, 4H), 2.20 (s, 3H), 2.07 (s, 3H). HPLC-MS (ESI+):m/z 439.2 [20%, (M³⁵Cl+H)⁺], 221.0 [40%, (M³⁷Cl+H, 40%)²⁺], 220.2 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 439.2 [100%, (M³⁵Cl+H)⁺], 220.1 [50%,(M³⁵Cl+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₃H₂₇ClN₆O (M+H)⁺ 439.2007,found 439.2007.

5-Chloro-N⁴-[3-(1,1-dimethylethyl)]phenyl-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG1-184)

This was prepared from SG1-175 (50 mg) and 4-(4-methylpiperazino)aniline(32 mg) using the general method x. The crude reaction mixture wastriturated using EtOAc/hexanes to give the title compound as a lightbrown solid (22 mg, 29%). Mp: 212° C. (dec). HPLC: 95% [t_(R)=5.9 min,50% MeOH, 50% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆):δ 9.03 (s, 1H, disappeared on D₂O shake), 8.67 (s, 1H, disappeared onD₂O shake), 8.05 (s, 1H), 7.65 (d, J=6.4 Hz, 1H), 7.45 (s, 1H), 7.39 (d,J=8.7 Hz, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 6.74 (d,J=8.6 Hz, 2H), 3.04-2.95 (m, 4H), 2.44-2.38 (m, 4H), 2.19 (s, 3H), 1.24(s, 9H). HPLC-MS (ESI+): m/z 453.3 [20%, (M³⁷Cl+H)⁺], 451.3 [70%,(M³⁵Cl+H)⁺], 227.1 [30%, (M³⁷Cl+2H)²⁺], 226.3 [100%, (M³⁵Cl+2H)²⁺].LC-MS (ESI+): 451.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₅H₃₁ClN₆ (M+H)⁺ 451.2371, found 451.2372.

5-Chloro-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-004)

This was prepared from SG2-003 (50 mg) and 4-(4-methylpiperazino)aniline(26 mg) using the general method x. The crude reaction mixture wastriturated using EtOAc/hexanes to give the title compound as a lightbrown solid (49 mg, 66%). Mp: 195° C. (dec). HPLC: 95% [t_(R)=9.9 min,35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆):δ 9.08 (s, 2H, disappeared on D₂O shake), 8.11 (s, 1H), 8.08-7.95 (m,2H), 7.62-7.47 (m, 3H; 1H disappeared on D₂O shake), 7.37 (d, J=7.6 Hz,2H), 6.78 (d, J=7.6 Hz, 2H), 3.23 (m, 1H), 3.06-2.94 (m, 4H), 2.45-2.36(m, 4H), 2.19 (s, 3H), 0.94 (d, J=5.7 Hz, 6H). HPLC-MS (ESI+): m/z 516.2[80%, (M³⁵Cl+H)⁺], 259.4 [50%, (M³⁷Cl+2H)²⁺], 258.7 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 516.1 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₄H₃₀ClN₇O₂S (M+H)⁺ 516.1943, found 516.1924.

5-Chloro-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-morpholinophenyl]pyrimidine-2,4-diamine(SG2-005-01)

This was prepared from SG1-149 (50 mg) and 4-morpholinoaniline (24 mg)using the general method x. The crude reaction product was purified viaflash chromatography using hexanes/EtOAc (30-40%) to give the titlecompound as a brown solid (18 mg, 26%). Mp: 236° C. (dec). HPLC: 90%[t_(R)=9.3 min, 50% MeOH, 50% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.10 (s, 1H, disappeared on D₂O shake), 9.08 (s,1H, disappeared on D₂O shake), 8.12 (s, 1H), 8.09-7.96 (m, 2H), 7.56 (s,1H, disappeared on D₂O shake), 7.54 (d, J=7.9 Hz, 1H), 7.49 (t, J=7.8Hz, 1H), 7.41 (d, J=8.7 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 3.74-3.66 (m,4H), 3.03-2.93 (m, 4H), 1.09 (s, 9H). HPLC-MS (ESI+): m/z 517.2 [100%,(M³⁵Cl+H)⁺], 259.1 [10%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 539.2 [45%,(M³⁵Cl+Na)⁺], 517.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₄H₂₉ClN₆O₃S (M+H)⁺ 517.1783, found 517.1775.

5-Chloro-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N₂-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-015-01)

This was obtained as a light yellow solid (50 mg, 35%) from SG1-149 (100mg) and 4-(4-methylpiperazino)aniline (51 mg) using the general methodx. Mp: 208° C. (dec). HPLC: 90% [t_(R)=4.8 min, 45% MeOH, 55% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.08 (s, 1H,disappeared on D₂O shake), 9.07 (s, 1H, disappeared on D₂O shake), 8.11(s, 1H), 8.08-7.95 (m, 2H), 7.57-7.54 (m, 2H; 1H disappeared on D₂Oshake), 7.49 (t, J=7.9 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.8Hz, 1H), 3.06-2.96 (m, 4H), 2.49-2.42 (m, 4H), 2.22 (s, 3H), 1.09 (s,9H). HPLC-MS (ESI+): m/z 530.3 [60%, (M³⁵Cl+H)⁺], 266.3 [30%,(M³⁷Cl+2H)²⁺], 265.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 530.2 [100%,(M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₂ClN₇O₂S (M+H) 530.2099,found 530.2092.

5-Methyl-N⁴-[3-(1,1-dimethylethyl)]phenyl-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-016)

This was prepared from SG2-013 (50 mg) and 4-(4-methylpiperazino)aniline(35 mg) using the general method x. The crude reaction mixture wastriturated using EtOAc/hexanes to give the title compound as a lightbrown solid (38 mg, 49%). Mp: 221° C. (dec). HPLC: 98% [t_(R)=11.3 min,45% MeOH, 55% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆):δ 8.65 (s, 1H, disappeared on D₂O shake), 8.12 (s, 1H, disappeared onD₂O shake), 7.80 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.46 (d, J=9.0 Hz,2H), 7.43 (t, J=1.8 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.06 (d, J=7.8 Hz,1H), 6.74 (d, J=9.0 Hz, 2H), 3.02-2.94 (m, 4H), 2.44-2.38 (m, 4H), 2.19(s, 3H), 2.07 (s, 3H), 1.25 (s, 9H). HPLC-MS (ESI+): m/z 431.3 [30%,(M+H)⁺], 216.3 [100%, (M+2H)²⁺]. LC-MS (ESI+): 431.3 [100%, (M+H)⁺].HRMS (ESI+): m/z calcd for C₂₆H₃₄N₆ (M+H)⁺ 431.2918, found 431.2913.

3-(2-[4-(4-Aminophenyl)piperazin-1-yl]-5-bromopyrimidin-4-yl)amino)-N-isopropylbenzenesulfonamide(MA1-014)

This was obtained as a gray solid solid (51 mg, 78%) from MA1-001 (50mg) and 4-(4-methylpiperazino)aniline (23 mg) using the general methodx. Mp: 275° C. (dec). HPLC: 99% [t_(R)=14.0 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.81 (s, 1H,disappeared on D₂O shake), 8.40 (t, J=1.9 Hz, 1H), 8.18 (s, 1H), 7.75(ddd, J=7.9, 1.9, 1.3 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H disappeared on D₂Oshake), 7.51 (t, J=7.9 Hz, 1H), 7.46 (dt, J=7.9, 1.3 Hz, 1H), 6.69 (d,J=8.8 Hz, 2H), 6.48 (d, J=8.8 Hz, 2H), 4.60 (s, 2H, disappeared on D₂Oshake), 3.78-3.71 (m, 4H), 3.26-3.18 (m, 1H), 2.93-2.87 (m, 4H), 0.93(d, J=6.5 Hz, 6H). HPLC-MS (ESI+): m/z 548.1 [100%, (M⁸¹Br+H)⁺], 546.2[97%, (M⁷⁹Br)⁺], 273.3 [10%, (M⁷⁹Br+2H)²⁺]. LC-MS (ESI+): 548.1 [100%,(M⁸¹Br+H)⁺], 546.1 [90%, (M⁷⁹Br+H)⁺]. HRMS (ESI+): m/z calcd forC₂₃H₂₈BrN₇O₂S (M+H)⁺ 546.1281, found 546.1263.

5-Ethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N₂-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-020)

This was obtained as a gray solid (26 mg, 38%) from MA1-013 (50 mg) and4-(4-methylpiperazino)aniline (32 mg) using the general method x. Mp:244° C. (dec). HPLC: 93% [t_(R)=7.9 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H, disappeared onD₂O shake), 8.57 (s, 1H, disappeared on D₂O shake), 8.19 (d, J=8.0 Hz,1H), 8.03 (brs, 1H), 7.90 (s, 1H), 7.61 (d, J=7.1 Hz, 1H, disappeared onD₂O shake), 7.54-7.42 (m, 4H), 6.80 (d, J=9.1 Hz, 2H), 3.30-3.18 (m,1H), 3.11-2.98 (m, 4H), 2.57 (q, J=7.4 Hz, 2H), 2.50-2.43 (m, 4H,overlapped with the residual DMSO signal) 2.25 (s, 3H), 1.16 (t, J=7.4Hz, 3H), 0.97 (d, J=6.6 Hz, 6H). HPLC-MS (ESI+): m/z 510.3 [25%,(M+H)⁺], 255.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): m/z 510.3 [100%, (M+H)⁺],255.6 [15%, (M+2H)²⁺], HRMS (ESI+): m/z calcd for C₂₈H₃₅N₇O₂S (M+H)⁺510.2646, found 510.2631.

5-Bromo-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)-N²-[4-morpholinophenyl]pyrimidine-2,4-diamine(MA1-021)

This was obtained as a white solid (46 mg, 70%) from MA1-001 (50 mg) and4-morpholinoaniline (21 mg) using the general method x. Mp: 220° C.(dec). HPLC: 99% [t_(R)=5.4 min, 50% MeOH, 50% water (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (s, 1H, disappeared on D₂Oshake), 8.86 (s, 1H, disappeared on D₂O shake), 8.19 (s, 1H), 7.96 (brs,2H), 7.58 (d, J=7.1 Hz, 1H, disappeared on D₂O shake), 7.55-7.51 (m,2H), 7.38 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 3.74-3.68 (m, 4H),3.21 (septet, J=6.5 Hz, 1H), 3.00-2.95 (m, 4H), 0.93 (d, J=6.5 Hz, 6H).HPLC-MS (ESI+): m/z 549.1 [100%, (M⁸¹Br+H)⁺], 548.2 [30%, (M⁸¹Br+H)⁺],547.2 [97%, (M⁷⁹Br+H)⁺]. LC-MS (ESI+): 549.1 [100%, (M⁸¹Br+H)⁺], 547.1[90%, (M⁷⁹Br+H)⁺]. HRMS (ESI+): m/z calcd for C₂₃H₂₇BrN₆O₃S (M+H)⁺547.1121, found 547.1102.

5-Ethyl-N⁴-(3-[N⁴-(1-methylethyl)sulfamoyl]phenyl)-N²-[4-morpholinophenyl]pyrimidine-2,4-diamine(MA1-022)

This was obtained as a gray solid (26 mg, 38%) from MA1-013 (50 mg) and4-morpholinoaniline (25 mg) using the general method x. Mp: 235° C.(dec). HPLC: 99% [t_(R)=6.2 min, 50% MeOH, 50% water (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H, disappeared on D₂Oshake), 8.55 (s, 1H, disappeared on D₂O shake), 8.17 (d, J=7.7 Hz, 1H),8.01 (s, 1H), 7.89 (s, 1H), 7.59 (d, J=7.1 Hz, 1H, disappeared on D₂Oshake), 7.51-7.42 (m, 4H), 6.79 (d, J=9.1 Hz, 2H), 3.74-3.67 (m, 4H),3.25-3.18 (m, 1H), 3.02-2.93 (m, 4H), 2.55 (q, J=7.4 Hz, 2H), 1.14 (t,J=7.4 Hz, 3H), 0.95 (d, J=6.5 Hz, 6H). HPLC-MS (ESI+): m/z 497.3 [100%,(M+H,)⁺], 249.1 [49%, (M+2H)²⁺]. LC-MS (ESI+): 497.2 [100%, (M+H)⁺].HRMS (ESI+): m/z calcd for C₂₅H₃₂N₆O₃S (M+H)⁺ 497.2329, found 497.2322.

5-Chloro-N⁴-[3-(1,1-dimethylethyl)phenyl]-N²-[4-morpholinophenyl]pyrimidine-2,4-diamine(MA1-023)

This was prepared from SG1-175 (50 mg) and 4-morpholinoaniline (32 mg)using the general method x. No purification was required to get thefinal product as a white solid (78 mg, 99%). Mp: 189° C. (dec). HPLC:99% [t_(R)=13.0 min, 65% MeOH, 35% water (with 0.1% TFA), 20 min]. ¹HNMR (400 MHz, DMSO-d₆): δ 9.05 (s, 1H, disappeared on D₂O shake), 8.68(s, 1H, disappeared on D₂O shake), 8.06 (s, 1H), 7.65 (d, J=7.5 Hz, 1H),7.46 (t, J=1.9 Hz, 1H), 7.42 (d, J=9.0 Hz, 2H), 7.26 (t, J=7.9 Hz, 1H),7.14 (ddd, J=7.9, 1.6, 0.9 Hz, 1H), 6.75 (d, J=9.0 Hz, 2H), 3.72-3.68(m, 4H), 2.99-2.95 (m, 4H), 1.25 (s, 9H). HPLC-MS (ESI+): m/z 440.2[35%, (M³⁷Cl+H)⁺], 438.2 [100%, (M³⁵Cl+H)⁺]. LC-MS (ESI+): 440.2 [30%,(M³⁷Cl+H)⁺], 438.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₄H₂₈ClN₅₀ (M+H) 438.2055, found 438.2074.

5-Bromo-N⁴(3-[N-(1-Methylethyl)sulfamoyl]phenyl)-N²-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-027)

This was obtained by stirring MA1-001 (90 mg) and4-(4-tert-butoxycarbonylpiperazino)aniline (62 mg) in isopropanol (2 mL)at 80° C. (oil bath) for 2 days. The reaction mixture was allowed tocool to room temperature and diluted with ethyl acetate (30 mL). Themixture was washed with NaHCO₃ (sat. aq. solution, 20 mL), brine (20 mL)and water (20 mL). The organic layer was dried (Na₂SO₄), and the solventevaporated under reduced pressure. The residue was purified by columnchromatography (SiO₂) eluting with ethyl acetate and hexane to provideMA1-027 as a dark grey solid (64 mg, 45%). Mp: 196-197° C. HPLC: 99%[t_(R)=12.8 min, 60% MeOH, 40% water (with 0.1% TFA), 30 min]. ¹H NMR(400 MHz, DMSO-d₆) δ 9.13 (s, 1H, disappeared on D₂O shake), 8.86 (s,1H, disappeared on D₂O shake), 8.19 (s, 1H), 8.02-7.92 (brs, 2H), 7.58(d, J=7.1 Hz, 1H, disappeared on D₂O shake), 7.55-7.50 (m, 2H), 7.38 (d,J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 3.45-3.38 (m, 4H), 3.21 (septet,J=6.5 Hz, 1H), 2.98-2.91 (m, 4H), 1.40 (s, 9H), 0.93 (d, J=6.5 Hz, 6H).HPLC-MS (ESI+): m/z 648.2 [100%, (M⁸¹Br+H)⁺], 646.2 [84%, (M⁷⁹Br+2H)⁺].LC-MS (ESI+): 670.2 [30%, (M⁸¹Br+H)⁺], 668.2 [30%, (M⁷⁹Br+2H)⁺], 648.2[100%, (M⁸¹Br+H)⁺], 646.2 [90%, (M⁷⁹Br+2H)⁺]. HRMS (ESI+): m/z calcd forC₂₈H₃₆BrN₇O₄S (M+H)⁺ 646.1806, found 646.1787.

5-Bromo-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)-N²-[4-(piperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-027-2)

This was prepared by overnight stirring of MA1-027 (41 mg) in 20%TFA/DCE (1.2 mL) at 80° C. Upon cooling to room temperature, thereaction mixture was poured into aq. NaHCO₃ and extracted with ethylacetate (2×40 mL). Column chromatography with DCM/MeOH (0-15%) yieldedMA1-027-2 as a golden white solid (22 mg, 64%). Mp: 233° C. (dec). HPLC:99% [t_(R)=5.2 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.09 (s, 1H, disappeared on D₂O shake), 8.85 (s,1H, disappeared on D₂O shake), 8.18 (s, 1H), 7.96 (brs, 2H), 7.58 (d,J=7.1 Hz, 1H, disappeared on D₂O shake), 7.55-7.50 (m, 2H), 7.35 (d,J=8.9 Hz, 2H), 6.75 (d, J=8.9 Hz, 2H), 3.22 (septet, J=6.5 Hz, 1H),2.97-2.90 (m, 4H), 2.86-2.78 (m, 4H), 0.93 (d, J=6.5 Hz, 6H). HPLC-MS(ESI+): m/z 546.2 [100%, (M⁷⁹Br+H⁺], 100%)⁺, 274.6 [97%, (M⁸¹Br+H)²⁺],273.6 [100%, (M⁷⁹Br+2H)]⁺². LC-MS (ESI+): 570.1 [20%, (M⁸¹Br+Na)⁺],568.1 [20%, (M⁷⁹Br+Na)⁺], 548.1 [100%, (M⁸¹Br+H)⁺], 546.1 [100%,(M⁷⁹Br+H)⁺]. HRMS (ESI+): m/z calcd for C₂₃H₂₈BrN₇O₂S (M+H)⁻ 546.1281,found 546.1276.

5-Ethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-morpholinophenyl]pyrimidine-2,4-diamine(MA1-028)

This was obtained as gray solid (25 mg, 38%) from MA1-017 (50 mg) and4-morpholinoaniline (23 mg) using the general method x. Mp: 214° C.(dec). HPLC: 99% [t_(R)=9.4 min, 50% MeOH, 50% water (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s, 1H, disappeared on D₂Oshake), 8.54 (s, 1H, disappeared on D₂O shake), 8.15-8.06 (m, 2H), 7.89(s, 1H), 7.56 (s, 1H, disappeared on D₂O shake), 7.50-7.44 (m, 4H), 6.80(d, J=9.1 Hz, 2H), 3.73-3.68 (m, 4H), 3.00-2.95 (m, 4H), 2.55 (q, J=7.4Hz, 2H), 1.14 (t, J=7.4 Hz, 3H), 1.10 (s, 9H). HPLC-MS (ESI+): m/z 511.3[100%, (M+H)⁺], 256.2 [55%, (M+H)²⁺]. LC-MS (ESI+): 511.2 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₄N₆O₃S (M+H)⁺ 511.2486, found511.2470.

5-Ethyl-N⁴-(3-[N-(1,1-Dimethylethyl)sulfamoyl]phenyl)-N²-[4-phenoxyphenyl]pyrimidine-2,4-diamine(MA1-030) and5-ethyl-N⁴-[(3-sulfamoyl)phenyl]-N²-[4-phenoxyphenyl]pyrimidine-2,4-diamine(MA1-030B)

This was prepared from MA1-017 (50 mg) and 4-morpholinoaniline (25 mg)using the general method x. The residue was purified via flashchromatography eluting with ethyl acetate-hexane to provide MA1-030 (30mg, 43%) as a white solid. Mp: 256° C. (dec). HPLC: 99% [t_(R)=9.0 min,55% MeOH, 45% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆):δ 9.05 (s, 1H, disappeared on D₂O shake), 8.64 (s, 1H, 65% reduced onD₂O shake), 8.12-8.08 (m, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.65 (d,J=9.0 Hz, 2H), 7.56 (s, 1H, disappeared on D₂O shake), 7.50-7.47 (m,2H), 7.37-7.31 (m, 2H), 7.09-7.03 (m, 1H), 6.94-6.90 (m, 2H), 6.87 (d,J=9.0 Hz, 2H), 2.59 (q, J=7.4 Hz, 2H), 1.15 (t, J=7.4 Hz, 3H), 1.10 (s,9H). HPLC-MS (ESI+): m/z 518.3 [100%, (M+H)⁺]. LC-MS (ESI+): 518.2[100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₁N₅O₃S (M+H)⁺ 518.2220,found 518.2215. Further elution gave the sulfonamide MA1-030B (18 mg,28%) as a white solid Mp: 281° C. (dec). HPLC: 99% [t_(R)=9.0 min, 55%MeOH, 45% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ9.03 (s, 1H, disappeared on D₂O shake), 8.65 (s, 1H, disappeared on D₂Oshake), 8.13-8.07 (m, 1H), 7.99 (brs, 1H), 7.93 (s, 1H), 7.64 (d, J=9.0Hz, 2H), 7.48-7.44 (m, 2H), 7.35-7.30 (m, 4H; 2H disappeared on D₂Oshake), 7.04 (tt, J=7.7, 1.1 Hz, 1H), 6.93-6.86 (m, 4H), 2.56 (q, J=7.4Hz, 2H), 1.15 (t, J=7.4 Hz, 3H). HPLC-MS (ESI+): m/z 462.1 [100%,(M+H)⁺]. LC-MS (ESI+): 462.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd forC₂₄H₂₃N₅O₃S (M+H)⁺ 462.1594, found 462.1589.

5-Ethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-032)

This was obtained as a light green solid (29 mg, 41%) from MA1-017 (50mg) and 4-(4-methylpiperazino)aniline (26 mg) using the general methodx. Mp: 220° C. (dec). HPLC: 90% [t_(R)=12.5 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 1H,disappeared on D₂O shake), 8.53 (s, 1H, disappeared on D₂O shake),8.15-8.10 (m, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H, disappearedon D₂O shake), 7.48-7.42 (m, 4H), 6.78 (d, J=9.1 Hz, 2H), 3.04-2.94 (m,4H), 2.55 (q, J=7.4 Hz, 2H), 2.45-2.36 (m, 4H), 2.19 (s, 3H), 1.14 (t,J=7.4 Hz, 3H), 1.10 (s, 9H). HPLC-MS (ESI+): m/z 524.3 [30%, (M+H)⁺],262.7 [100%, (M+H)²⁺]. LC-MS (ESI+): 524.3 [100%, (M+H)⁺]. HRMS (ESI+):m/z calcd for C₂₇H₃₇N₇O₂S (M+H)⁺ 524.2802, found 524.2787.

5-Methyl-N⁴-(4-[N-(1,1-Dimethylethyl)sulfamoyl]phenyl)-N²-[4-phenoxyphenyl]pyrimidine-2,4-diamine(MA1-033)

This was prepared from SG2-007 (50 mg) and 4-phenoxyaniline (26 mg)using the general method x. The residue was purified via chromatographyeluting with ethyl acetate-hexane (1:5-1:0, v/v) to provide MA1-033 (15mg, 21%) as beige solid. Mp: 276° C. (dec). HPLC: 94% [t_(R)=9.8 min,50% MeOH, 50% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆)δ 9.14 (s, 1H, disappeared on D₂O shake), 8.58 (s, 1H, disappeared onD₂O shake), 7.95 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.75-7.66 (m, 4H),7.38 (s, 1H, disappeared on D₂O shake), 7.36-7.29 (m, 2H), 7.03 (t,J=7.4 Hz, 1H), 6.96-6.86 (m, 4H), 2.12 (s, 3H), 1.03 (s, 9H). HPLC-MS(ESI+): m/z 504.3 [100%, (M+H)⁺]. LCMS (ESI+): 504.2 [100%, (M+H)⁺].HRMS (ESI+): m/z calcd for C₂₇H₂₉N₅O₃S (M+H) 504.2064, found 504.2047.

5,6-Dimethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(RJ1-014)

A mixture of RJ1-010 (0.050 g, 0.136 mmol),4-(4-methyl-1-piperazinyl)-aniline (0.026 g, 0.136 mmol), EtOH (1 mL,0.027 mol) and 4 M HCl (2 drops) was heated in a microwave reactor at160° C. for 15 minutes. The reaction mixture was dissolved in EtOAc (20mL) and washed with saturated NaHCO₃ (20 mL). The aqueous layer was thenre-extracted with EtOAc (20 mL). The combined organic layers were washedwith water (20 mL), brine (20 mL), dried over Na₂SO₄, and concentrated.The residue was then triturated with hexanes and EtOAc to provideRJ1-014 (0.041 g, 58%) as a powdery, off-white solid. Mp: 201 OC (dec).HPLC: 90% [t_(R)=8.8 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 1H, disappeared on D₂O shake),8.44 (s, 1H, disappeared on D₂O shake), 8.05-7.94 (m, 2H), 7.54 (s, 1H),7.49-7.41 (m, 4H), 6.76 (d, J=9.0 Hz, 2H), 3.04-2.93 (m, 4H), 2.45-2.38(m, 4H), 2.25 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H), 1.10 (s, 9H). HPLC-MS(ESI+): m/z 524.2 [90%, (M+H)⁺], 262.8 [100%, (M+2H)²⁺]. LC-MS (ESI+):524.3 [100%, (M+H)⁺], 262.6 [10%, (M+2H)²⁺], 234.6 [40%, (M+2H-tBu)²⁺].HRMS (ESI+): m/z calcd for C₂₇H₃₇N₇O₂S (M+H)⁺ 524.2802, found 524.2791.

5,6-Dimethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-morpholinophenyl]pyrimidine-2,4-diamine(RJ1-024-01)

A mixture of RJ1-010 (0.100 g, 0.271 mmol), 4-morpholinoaniline (0.048g, 0.271 mmol), EtOH (2 mL), and 4M HCl (3 drops) was allowed to reactand worked up following the same procedure as used for RJ1-014. Theresidue was purified via flash chromatography eluting with DCM (with 2%MeOH) to provide RJ1-024-01 (0.037 g, 27%) as a pale lilac solid. Mp:222° C. (dec). HPLC 99.9% [t_(R)=8.2 min, 45% MeOH (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.69 (s, 1H, disappeared on D₂Oshake), 8.44 (s, 1H, disappeared on D₂O shake), 8.05-7.97 (m, 2H), 7.54(s, 1H, disappeared on D₂O shake), 7.47 (d, J=9.0 Hz, 2H), 7.45-7.42 (m,2H), 6.78 (d, J=9.0 Hz, 2H), 3.74-3.65 (m, 4H), 3.00-2.93 (m, 4H), 2.26(s, 3H), 2.09 (s, 3H), 1.10 (s, 9H). HPLC-MS (ESI+): m/z 511.3 [100%,(M+H)⁺], 256.3 [90%, (M+2H)²⁺]. LC-MS (ESI+): m/z 511.3 (M+H)⁺; HRMS(ESI+): m/z calcd for C₂₆H₃₄N₆O₃S (M+H) 511.2486, found 511.2485.

5,6-Dimethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-(4-methoxyphenyl)pyrimidine-2,4-diamine(RJ1-027-01) and5,6-dimethyl-N⁴-[3-(sulfamoyl)phenyl]-N²-[4-methoxyphenyl]pyrimidine-2,4-diamine(RJ1-027-02)

A mixture of RJ1-010 (0.100 g, 0.271 mmol), p-anisidine (0.033 g, 0.271mmol), EtOH (2 mL), and 4M HCl (3 drops) was allowed to react and workedup following the same procedure as with RJ1-014. The residue was thenpurified via flash chromatography, eluting with DCM (with 2% MeOH) toprovide RJ1-027-01, as a white solid (0.041 g, 33%). Mp: 224° C. (dec).HPLC 95% [t_(R)=10.6 min, 45% MeOH, 55% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H, disappeared on D₂O shake),8.46 (s, 1H, disappeared on D₂O shake), 8.04-7.98 (m, 2H), 7.55-7.43 (m,5H), 6.74 (d, J=9.0 Hz, 2H), 3.67 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H),1.09 (s, 9H). HPLC-MS (ESI+): m/z 456.2 (100%, M+H)⁺]. LC-MS (ESI+): m/z456.3 (M+H)⁺. HRMS (ESI+): m/z calcd for C₂₃H₂₉N₅O₃S (M+H)⁺ 456.2064,found 456.2059. Further elution from the column using DCM (with 3-4%MeOH) gave RJ1-027-02 as a white solid, (0.006 g, 5%). Mp: 216° C.(dec). HPLC 94% [t_(R)=7.4 min, 35% MeOH, 65% water (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H, disappeared on D₂Oshake), 8.49 (s, 1H, disappeared on D₂O shake), 8.08-7.99 (m, 1H), 7.96(brs, 1H), 7.52 (d, J=9.0 Hz, 2H), 7.47-7.43 (m, 2H), 7.32 (s, 2H,disappeared on D₂O shake), 6.75 (d, J=9.0 Hz, 2H), 3.67 (s, 3H), 2.26(s, 3H), 2.09 (s, 3H). HPLC-MS (ESI+): m/z 400.2 (100%, M+H)⁺]. LC-MS(ESI+): m/z 400.1 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₁₉H₂₁N₅O₃S(M+H)⁺ 400.1438, found 400.1446.

5,6-Dimethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(2-hydroxyethylcarbamoyl)phenyl]pyrimidine-2,4-diamine(RJ1-030-01)

A mixture of RJ1-010 (0.100 g, 0.271 mmol,N-(4-aminobenzoyl)aminoethanol (0.033 g, 0.271 mmol), EtOH (2 mL), and4M HCl (3 drops) was allowed to react and worked up following the sameprocedure used to make RJ1-014. The residue was then purified via flashchromatography eluting with DCM (with 6% MeOH) to provide RJ1-030-01 asa white foam (0.030 g, 22%). Mp: 174 OC (decomposed). HPLC 97%[t_(R)=6.0 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.25 (s, 1H, disappeared on D₂O shake), 8.60 (s,1H, disappeared on D₂O shake), 8.15 (t, J=5.5 Hz, 1H, disappeared on D₂Oshake), 8.05-7.96 (m, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz,2H), 7.57-7.45 (m, 3H), 4.71 (t, J=5.3 Hz, 1H, disappeared on D₂Oshake), 3.49-3.42 (m, 2H), 3.30-3.23 (m, 2H), 2.31 (s, 3H), 2.12 (s,3H), 1.10 (s, 9H). HPLC-MS (ESI+): m/z 535.2 [100%, (M+H)⁺]. LC-MS(ESI+): m/z 535.2 [40%, (M+Na)⁺], 513.2 [100%, (M+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₅H₃₂N₆O₄S (M+H)⁺ 513.2279, found 513.2291.

5-Methyl-N⁴-(3-Cyclopropylsulfonamido)phenyl-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(RJ1-036-01)

A mixture of RJ1-032 (0.100 g, 0.295 mmol),4-(4-methyl-1-piperazinyl)aniline (0.056 g, 0.295 mmol), EtOH (2 mL),and 4M HCl (3 drops) was reacted and worked up following the sameprocedure as with RJ1-014. The residue was then purified via flashchromatography eluting with MeOH (6-7%) in DCM to give the productRJ1-036-01 as a beige-colored solid, (0.052 g, 36%). Mp: 124° C. (dec).HPLC 99% [t_(R)=9.7 min, 30% MeOH, 70% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.70-9.60 (brs, 1H, disappeared on D₂Oshake), 8.58 (s, 1H, disappeared on D₂O shake), 8.30 (s, 1H, disappearedon D₂O shake), 7.83 (d, J=0.7 Hz, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.46 (d,J=9.0 Hz, 2H), 7.22 (t, J=8.3 Hz, 1H), 6.94-6.85 (m, 1H), 6.77 (d, J=9.1Hz, 2H), 3.02-2.96 (m, 4H), 2.63-2.54 (m, 1H), 2.46-2.36 (m, 4H), 2.19(s, 3H), 2.07 (s, 3H), 0.92 (m, 4H). HPLC-MS (ESI+): m/z 494.3 [20%,(M+H)]; 247.8 [100%, (M+2H)²⁺], LC-MS (ESI+): m/z 494.2 [100%, (M+H)⁺],247.6 [25%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₁N₇O₂S (M+H)⁺494.2333, found 494.2331.

N⁴-(4-Chloro-3-methoxyphenyl)-5,6-dimethyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(RJ1-040-01)

A mixture of RJ1-034 (0.050 g, 0.168 mmol),4-(4-methyl-1-piperazinyl)aniline (0.032 g, 0.168 mmol), EtOH (1 mL),and 4M HCl (2 drops) was allowed to react and worked up following thesame procedure used to prepare RJ1-014. The residue was purified viaflash chromatography eluting with MeOH (4%) in DCM to provide thedesired product as an off-white solid, RJ1-040-01 (0.012 g, 16%). Mp:157° C. (dec). HPLC 99.8% [t_(R)=8.4 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.69 (s, 1H, disappeared onD₂O shake), 8.21 (s, 1H, disappeared on D₂O shake), 7.45 (d, J=9.0 Hz,2H), 7.41 (d, J=2.2 Hz, 1H), 7.33 (dd, J=8.6, 2.2 Hz, 1H), 7.25 (d,J=8.6 Hz, 1H), 6.74 (d, J=9.1 Hz, 2H), 3.68 (s, 3H), 3.02-2.97 (m, 4H),2.46-2.40 (m, 4H), 2.24 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H). HPLC-MS(ESI+): m/z 453.2 [15%, (M³⁵Cl+H)⁻], 227.9 [40%, (M³⁷Cl+2H)²⁺]. 227.2[100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): m/z 455.2 [35%, (M³⁷Cl+H)⁺], 453.2[100%, (M³⁵Cl+H)⁻], 227.1 [25%, (M³⁵Cl+2H)²⁺]. HRMS (ESI+): m/z calcdfor C₂₄H₂₉ClN₆O (M+H) 453.2164, found 453.2155.

5,6-Dimethyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁴-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine(RJ1-041-01)

A mixture of RJ1-037 (0.100 g, 0.309 mol),4-(4-methyl-1-piperazinyl)aniline (0.059 g, 0.309 mol), EtOH (2 mL), and4M HCl (3 drops) was allowed to react and worked up following the sameprocedure for RJ1-014. The residue was then purified via flashchromatography eluting with MeOH (5-6%) in DCM to gibe the desiredproduct as a champagne-colored solid, RJ1-041-01 (0.054 g, 36%). Mp:137° C. (dec). HPLC 99% [t_(R)=5.5 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 1H, disappeared onD₂O shake), 8.05 (s, 1H, disappeared on D₂O shake), 7.48 (d, J=9.0 Hz,2H), 6.90 (s, 2H), 6.70 (d, J=9.0 Hz, 2H), 3.63 (s, 9H), 3.00-2.91 (m,4H), 2.44-2.40 (m, 4H), 2.23 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H).HPLC-MS (ESI+): m/z 479.3 [15%, (M+H)⁺], 240.3 [100%, (M+2H)²⁺]. LC-MS(ESI+): m/z 479.3 [100%, (M+H)⁺], 240.1 [40%, (M+2H)²⁺], HRMS (ESI+):m/z calcd for C₂₆H₃₄N₆O₃ (M+H)⁺ 479.2765, found 479.2768.

5-Methyl-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-021-03)

This was obtained as a tangerine-colored solid (24 mg, 33%) from SG2-014(50 mg) and 4-(4-methylpiperazino)aniline (28 mg) using the generalmethod x. Mp: 192° C. (dec). HPLC: 99% [t_(R)=7.8 min, 35% MeOH, 65%water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (s,1H, disappeared on D₂O shake), 8.52 (s, 1H, disappeared on D₂O shake),8.19 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.59 (d, J=7.1 Hz,1H), 7.52-7.38 (m, 4H; 1H disappeared on D₂O shake), 6.79 (d, J=9.0 Hz,2H), 3.22 (septet, J=6.4 Hz, 1H), 3.03-2.96 (m, 4H), 2.46-2.41 (m, 4H),2.20 (s, 3H), 2.09 (s, 3H), 0.95 (d, J=6.5 Hz, 6H). HPLC-MS (ESI+): m/z496.3 [20%, (M+H)⁺], 248.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 496.2 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₃N₇O₂S (M+H)⁺ 496.2489, found496.2474.

5-Trifluoromethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-029-01) (2 TFA salt)

The 4-chloropyrimidine SG2-022 was prepared using the previouslyreported method.¹ A solution of 2,4-dichloro-5-trifluoromethylpyrimidine(120 mg, 0.550 mmol) in t-BuOH/DCM (1:1, 4 mL) was cooled to 0° C. Zincchloride (1 M in diethyl ether, 0.633 mL, 0.633 mmol) was added dropwiseover 10 minutes at 0° C. and the solution stirred at the sametemperature for 30 minutes. A solution of tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate (145 mg, 0.523 mmol) int-BuOH/DCM (1:1, 2 mL) was added dropwise over 10 minutes at 0° C.followed by Et₃N (0.089 mL, 0.633 mmol) in t-BuOH/DCM (1:1, 2 mL). Themixture was warmed to room temperature and stirred for 24 hours. Thesolvent was removed under reduced pressure and water (20 mL) was added.The suspension was sonicated for 30 minutes and the precipitate wasfiltered, dried to provide SG2-022 (0.210 g) which was used in the nextstep without purification. The 4-chloropyrimidine SG2-022 (50 mg, 0.109mmol) and SG1-137 (25 mg, 0.109 mmol) and HCl (aq. 37%, 0.067 mL, 0.818mmol) were mixed in EtOH (1 mL) and stirred at 85° C. for 2 hours. Thereaction mixture was diluted with EtOAc (20 mL) and washed withsaturated NaHCO₃ (20 mL). The aqueous layer was then re-extracted withEtOAc (20 mL). The combined organic layers were washed with water andbrine (20 mL each), dried over Na₂SO₄, and concentrated under reducedpressure. The residue was triturated with hexanes/EtOAc and providedSG2-024 (0.046 g) as an off-white solid which was used in the next stepwithout purification. To a solution of SG2-024 (40 mg, 0.073 mmol) indry MeOH (1 mL) was added formaldehyde (37% aq. solution, 0.024 ml,0.328 mmol) and sodium triacetoxyborohydride (0.077 mg, 0.364 mmol). Thereaction mixture was stirred at room temperature for 2 hours. Thesolvent was removed under reduced pressure and the residue was dilutedwith EtOAc (10 mL) and washed with saturated NaHCO₃ (15 mL). The aqueouslayer was then re-extracted with EtOAc (10 mL). The combined organiclayers were washed with water and brine (10 mL each), dried over Na₂SO₄,and concentrated under reduced pressure. The resulting crude oil waspurified via HPLC eluting with 35% MeCN and 65% water (with 0.1% TFA) toprovide the title compound SG2-029-01 as light brown thin film (8 mg,20%). HPLC: 99% [t_(R)=6.6 min, 50% MeOH, 50% water (with 0.1% TFA), 20min]. ¹H NMR at 80° C. (400 MHz, DMSO-d₆): δ 9.22 (s, 1H, disappeared onD₂O shake), 8.62 (s, 1H, disappeared on D₂O shake), 8.32 (s, 1H), 7.89(s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.51 (t, J=8.1Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.18 (s, 1H, disappeared on D₂O shake),6.80 (d, J=9.0 Hz, 2H), 2.85 (s, 3H), 1.13 (s, 9H). ¹⁹F NMR (376 MHz,DMSO-d₆): δ −58.61 (s, 3F), −73.54 (s, 6F). HPLC-MS (ESI+): m/z 564.3[100%, (M+H)⁺], 282.7 [40%, (M+2H)²⁺]. LC-MS (ESI+): 564.2 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₂F₃N₇O₂S (M+H)⁻ 564.2363, found564.2370.

5-Trifluoromethyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(piperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-033-01-1) (3 TFA salt)

To a solution of SG2-022 (100 mg, 0.218 mmol) and SG1-137 (50 mg, 0.218mmol) in EtOH (1 mL) was added 3 drops of 4 M HCl (aq). The mixture wasstirred at 85° C. for 2 hours. The solution was diluted with EtOAc (40mL) and washed with saturated NaHCO₃ (40 mL). The aqueous layer was thenre-extracted with EtOAc (40 mL). The combined organic layers were washedwith water and brine (40 mL each), dried over Na₂SO₄, and concentratedunder reduced pressure to provide a crude oil. The crude oil waspurified via HPLC eluting with 30% MeCN and 70% water (with 0.1% TFA) toprovide the title compound SG2-033-01-1 as a yellow solid (35 mg, 29%).Mp: 183° C. (dec). HPLC: 99% [t_(R)=6.8 min, 50% MeOH, 50% water (with0.1% TFA), 20 min]. ¹H NMR at 80° C. (400 MHz, DMSO-d₆): δ 9.22 (s, 1H,disappeared on D₂O shake), 8.62 (s, 1H, disappeared on D₂O shake), 8.60(br s, 1H, disappeared on D₂O shake), 8.33 (s, 1H), 7.89 (s, 1H), 7.77(d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.37(d, J=8.7 Hz, 2H), 7.18 (s, 1H, disappeared on D₂O shake), 6.79 (d,J=8.7 Hz, 2H), 1.13 (s, 9H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −59.20 (3F),−74.25 (9F). HPLC-MS (ESI+): m/z 550.3 [100%, (M+H)⁺], 275.7 [50%,(M+2H)²⁺]. LC-MS (ESI+): 572.2 [15%, (M+Na)⁺], 550.2 [100%, (M+H)⁺].HRMS (ESI+): m/z calcd for C₂₅H₃₀F₃N₇O₂S (M+H)⁺ 550.2207, found550.2194.

5-Chloro-N⁴-(3,4,5-trimethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-054-01)

This was obtained as a light yellow oil (30 mg, 41%) from SG2-047 (50mg) and 4-(4-methylpiperazino)aniline (29 mg) using the general methodx. HPLC: 96% [t_(R)=8.6 min, 35% MeOH, 65% water (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.06 (s, 1H, disappeared on D₂Oshake), 8.66 (s, 1H, disappeared on D₂O shake), 8.05 (s, 1H), 7.41 (d,J=9.0 Hz, 2H), 6.94 (s, 1H), 6.73 (d, J=8.9 Hz, 2H), 3.64 (s, 9H),3.04-2.94 (m, 4H), 2.44-2.39 (m, 4H), 2.19 (s, 3H). HPLC-MS (ESI+): m/z485.3 [40%, (M³⁵Cl+H)⁺], 244.2 [40%, (M³⁷Cl+2H)²⁺], 243.2 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 485.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₄H₂₉ClN₆O₃ (M+H)⁺ 485.2062, found 485.2058.

5-Chloro-N⁴-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-055-01)

This was obtained as a brown-yellow solid (29 mg, 38%) from SG2-048 (50mg) and 4-(4-methylpiperazino)aniline (32 mg) using the general methodx. Mp: 220° C. (dec). HPLC: 99% [t_(R)=8.6 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.03 (s, 1H,disappeared on D₂O shake), 8.57 (s, 1H, disappeared on D₂O shake), 8.01(s, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.19 (d, J=2.0 Hz, 1H), 7.05 (dd,J=8.7, 2.0 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H),4.27-4.17 (m, 4H), 3.10-2.96 (m, 4H), 2.46-2.37 (m, 4H), 2.19 (s, 3H).HPLC-MS (ESI+): m/z 453.2 [40%, (M³⁵Cl+H)⁺ ]; 228.2 [40%, (M³⁷Cl+2H)²⁺],227.2 [100%, (M³⁵Cl+2H)^(2+]). LC-MS (ESI+): 453.2 [100%, (M³⁵Cl+H)⁺].HRMS (ESI+): m/z calcd for C₂₃H₂₅ClN₆O₂ (M+H)⁺ 453.1800, found 453.1812.

5-Chloro-N⁴-(benzo[d][1,3]dioxol-5-yl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-056)

This was obtained as a light magenta solid (45 mg, 58%) from SG2-049 (50mg) and 4-(4-methylpiperazino)aniline (34 mg) using the general methodx. Mp: 175° C. (dec). HPLC: 86% [t_(R)=7.8 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.04 (s, 1H,disappeared on D₂O shake), 8.64 (s, 1H, disappeared on D₂O shake), 8.02(s, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.29 (s, 1H), 7.02 (d, J=8.4 Hz, 1H),6.87 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 6.01 (s, 2H), 3.05-2.98(m, 4H), 2.47-2.41 (m, 4H), 2.20 (s, 3H). HPLC-MS (ESI+): m/z 441.2[20%, (M³⁷Cl+H)⁺], 439.2 [50%, (M³⁵Cl+H)⁺], 221.1 [40%, (M³⁷Cl+2H)²⁺],220.2 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 439.1 [100%, (M³⁵Cl+H)⁺]. HRMS(ESI+): m/z calcd for C₂₂H₂₃ClN₆O₂ (M+H)⁺ 439.1643, found 439.1637.

5-Chloro-N⁴-(4-chloro-2,5-dimethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-060-01)

This was obtained as an off-white solid (40 mg, 55%) from SG2-059 (50mg) and 4-(4-methylpiperazino)aniline (28 mg) using the general methodx. Mp: 232° C. (dec). HPLC: 99% [t_(R)=10.5 min, 45% MeOH, 55% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.08 (s, 1H,disappeared on D₂O shake), 8.15 (s, 1H, disappeared on D₂O shake), 8.09(s, 1H), 7.63 (brs, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.20 (s, 1H), 6.74 (d,J=8.5 Hz, 2H), 3.78 (s, 3H), 3.60 (s, 3H), 3.03-2.95 (m, 4H), 2.45-2.38(m, 4H), 2.20 (s, 4H). HPLC-MS (ESI+): m/z 491.2 [70%, (M³⁵Cl³⁷Cl+H)⁻],489.2 [100%, (M³⁵Cl³⁵Cl+H)⁺], 246.2 [70%, (M³⁵Cl³⁷Cl+2H)²⁺], 245.2[100%, (M³⁵Cl³⁵Cl+2H)²⁺]. LC-MS (ESI+): 489.1 (M³⁵Cl³⁵Cl+H)⁺. HRMS(ESI+): m/z calcd for C₂₃H₂₆Cl₂N₆O₂ (M+H)⁺ 489.1567, found 489.1552.

5-Ethyl-N⁴-[4-chloro-3-methoxyphenyl]-N₂-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-057)

This was obtained as a white solid (18 mg, 16%) from MA1-025 (74 mg) and4-(4-methylpiperazino)aniline (50 mg) using the general method x. Mp:244° C. (dec). HPLC: 100% [t_(R)=10.1 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (s, 1H,disappeared on D₂O shake), 8.33 (s, 1H, disappeared on D₂O shake), 7.88(s, 1H), 7.48 (d, J=2.2 Hz, 1H), 7.46 (d, J=9.1 Hz), 7.42 (dd, J=8.6,2.2 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 6.79 (d, J=9.1 Hz, 2H), 3.72 (s,3H), 3.07-3.01 (s, 4H), 2.55 (q, J=7.4 Hz, 2H), 2.53-2.45 (m, 4H), 2.28(s, 3H), 1.16 (t, J=7.4 Hz, 3H). HPLC-MS (ESI+): m/z 453.3 [20%,(M+H)⁻], 227.2 [100%, (M³⁵Cl+2H)²⁺], 227.9 [40%, (M³⁵Cl³⁷Cl+2H)²⁺].LC-MS (ESI+): 455.2 [35%, (M+H)⁺], 453.2 [100%, (M+H)⁺]. HRMS (ESI+):m/z calcd for C₂₄H₂₉ClN₆O (M+H)⁺ 453.2164, found 453.2154.

5-Chloro-N⁴-(3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-pyrimidine-2,4-diamine(MA1-063)

This was obtained as a light gray solid (39 mg, 50%) from MA1-055-1 (50mg) and 4-(4-methylpiperazino)aniline (37 mg) using the general methodx. Mp: 149° C. (dec). HPLC: 99% [t_(R)=9.7 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.11 (s, 1H,disappeared on D₂O shake), 8.69 (s, 1H, disappeared on D₂O shake), 8.09(s, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.32 (brd, J=7.9 Hz, 1H), 7.27 (t,J=1.9 Hz, 1H), 7.23 (t, J=8.2 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 6.69(ddd, J=8.2, 2.5, 0.8 Hz, 1H), 3.71 (s, 3H), 3.05 (brs, 4H), 2.47 (brs,4H, appeared from the solvent signal on D₂O shake) 2.26 (s, 3H). HPLC-MS(ESI+): m/z 425.3 [50%, (M³⁵Cl+H)⁺], 214.2 [100%, (M³⁷Cl+2H)²⁺], 213.2[40%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 425.2 [100%, (M³⁵Cl+H)⁺]. HRMS(ESI+): m/z calcd for C₂₂H₂₅ClN₆O (M+H)⁺ 425.1838, found 425.1851.

5-Chloro-N⁴-(3-ethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-pyrimidine-2,4-diamine(MA1-064)

This was obtained as a white solid (28 mg, 36%) from MA1-058 (50 mg) and4-(4-methylpiperazino)aniline (33.6 mg) using the general method x. Mp:133-139° C. HPLC: 96% [t_(R)=8.7 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.09 (s, 1H, disappeared onD₂O shake), 8.66 (s, 1H, disappeared on D₂O shake), 8.07 (s, 1H), 7.43(d, J=9.0 Hz, 2H), 7.26 (s, 1H), 7.23 (d, J=2.1 Hz, 1H), 7.20 (t, J=8.1Hz, 1H), 6.76 (d, J=9.1 Hz, 2H), 6.66 (dd, J=8.6, 2.0 Hz, 1H), 3.93 (q,J=6.9 Hz, 2H), 3.04-2.95 (m, 4H), 2.472.39 (m, 4H), 2.20 (s, 3H), 1.29(t, J=7.0 Hz, 3H). HPLC-MS (ESI+): m/z 441.3 [20%, (M³⁷Cl+H)⁺], 439.3[50%, (M³⁵Cl+H)⁺], 221.2 [100%, (M³⁷Cl+2H)²⁺], 220.2 [100%,(M³⁵Cl+2H)²′]. LC-MS (ESI+): 439.2 [100%, (M³⁵Cl+H)]. HRMS (ESI+): m/zcalcd for C₂₃H₂₇ClN₆O (M+H)⁺ 439.2008, found 439. 2007.

5-Methyl-N⁴-(3,4-Dimethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-065)

This was obtained as a white solid (36 mg, 46%) from MA1-062 (50 mg) and4-(4-methylpiperazino)aniline (34 mg) using the general method x. Mp:157-163° C. HPLC: 100% [t_(R)=6.9 min, 35% MeOH, 65% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 1H, disappeared onD₂O shake), 8.10 (s, 1H, disappeared on D₂O shake), 7.79 (s, 1H), 7.48(d, J=9.0 Hz, 2H), 7.25-7.20 (m, 2H), 6.89 (d, J=8.4 Hz, 1H), 6.75 (d,J=9.0 Hz, 2H), 3.75 (s, 3H), 3.66 (s, 3H), 3.05-2.99 (m, 4H), 2.53-2.45(m, 4H), 2.26 (s, 3H), 2.06 (s, 3H). HPLC-MS (ESI+): m/z 435.3 [20%,(M+H)⁺], 218.3 [100%, (M+2H)²⁻]. LC-MS (ESI+): 435.2 [100%, (M+H)⁻].HRMS (ESI+): m/z calcd for C₂₄H₃₀N₆O₂ (M+H)⁺ 435.2503, found 435.2516.

5-Chloro-N⁴-(3,4-dimethoxyphenyl)-M-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-066)

This was obtained as a dark grey solid (46 mg, 61%) from MA1-059 (50 mg)and 4-(4-methylpiperazino)aniline (31.9 mg) using the general method x.Mp: 163° C. (dec). HPLC: 99% [t_(R)=6.2 min, 35% MeOH, 65% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.03 (s, 1H,disappeared on D₂O shake), 8.65 (s, 1H, disappeared on D₂O shake), 8.03(s, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.21-7.14 (m, 2H), 6.91 (d, J=8.6 Hz,1H), 6.75 (d, J=9.0 Hz, 2H), 3.76 (s, 3H), 3.66 (s, 3H), 3.0-2.99 (m,4H), 2.47-2.42 (m, 4H), 2.21 (s, 3H). HPLC-MS (ESI+): m/z 457.3 [15%,(M³⁷Cl+H)⁺], 455.2 [40%, (M³⁵Cl+H)⁺], 229.0 [100%, (M³⁷Cl+2H)²⁺], 228.2[100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 455.2 [100%, (M³⁵Cl+H)⁺]. HRMS(ESI+): m/z calcd for C₂₃H₂₇ClN₆O₂ (M+H)⁺ 455.1957, found 455.1933.

5-Methyl-N⁴-(3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-067)

This was obtained as a gray solid (38 mg, 47%) from MA1-060 (50 mg) and4-(4-methylpiperazino)aniline (38.3 mg) using the general method x. Mp:139° C. (dec). HPLC: 98% [t_(R)=8.7 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. H NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 1H, disappeared onD₂O shake), 8.14 (s, 1H, disappeared on D₂O shake), 7.82 (s, 1H), 7.49(d, J=9.1 Hz, 2H), 7.35 (d, J=8.2 Hz, 1H), 7.30 (t, J=2.2 Hz, 1H), 7.18(t, J=8.2 Hz, 1H), 6.77 (d, J=9.1 Hz, 2H), 6.60 (ddd, J=8.2, 2.5, 0.8Hz, 1H), 3.69 (s, 3H), 3.05-2.97 (m, 4H), 2.50-2.45 (m, 4H, appearedfrom the solvent signal on D₂O Shake), 2.23 (s, 3H), 2.07 (s, 3H).HPLC-MS (ESI+): m/z 405.3 [20%, (M+H)⁺], 203.2 [100%, (M+2H)²⁺]. LC-MS(ESI+): 405.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₃H₂₈N₆O(M+H)⁺ 405.2397, found 405.2417.

5-Methyl-N⁴-[3-ethoxyphenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-068)

This was obtained as a white solid (26 mg, 33%) from MA1-061 (50 mg) and4-(4-methylpiperazino)aniline (36 mg) using the general method x. Mp:201° C. (dec). HPLC: 100% [t_(R)=3.5 min, 45% MeOH, 55% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 1H, disappeared onD₂O shake), 8.12 (s, 1H, disappeared on D₂O shake), 7.82 (s, 1H), 7.49(d, J=9.0 Hz, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.17(t, J=8.1 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 6.58 (dd, J=8.1, 2.0 Hz, 1H),3.93 (q, J=6.9 Hz, 2H), 3.04-2.98 (m, 4H), 2.50-2.45 (m, 4H, overlappedby the residual solvent signal), 2.23 (s, 3H), 2.07 (s, 3H), 1.28 (t,J=6.9 Hz, 3H). HPLC-MS (ESI+): m/z 419.2 [20%, (M+H)⁺], 210.3 [100%,(M+2H)²⁻]. LC-MS (ESI+): 419.2 [100%, (M+H)⁻], 210.3 [15%, (M+2H)²⁺].HRMS (ESI+): m/z calcd for C₂₄H₃₀N₆O (M+H) 419.2554, found 419.2567.

5-Isopropyl-N⁴,N²-bis-[3-(sulfamoyl)phenyl]pyrimidine-2,4-diamine(MA1-036B)

A mixture of SG1-137 (57 mg) and MA1-034-2 (47 mg) in dry MeOH (2 mL) ina 5 mL microwave vial were heated in microwave at 150° C. for 15minutes. Upon cooling to room temperature, and evaporation of themethanol the crude material was directly purified using columnchromatography (ethyl acetate-hexane) to provide the title compound as asolid (20 mg, 17%). Mp: 291° C. (dec). HPLC: 99% [t_(R)=7.5 min, 35%MeOH, 65% water (with 0.1% TFA), 20 min]. δ 10.27 (brs, 1H, disappearedon D₂O shake), 9.80 (brs, 1H, disappeared on D₂O shake), 7.95 (s, 1H),7.91-7.86 (m, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.74 (brs, 1H), 7.66 (d,J=7.6 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.50 (d, J=7.3 Hz, 1H), 7.45-7.35(m, 5H, 4H disappeared on D₂O shake), 3.21 (septet, J=6.7 Hz, 1H,partially overlapped by residual DMSO signal), 1.25 (d, J=6.7 Hz, 6H).HPLC-MS (ESI+): m/z 463.2 [100%, (M+H)⁺]. LC-MS (ESI+): 463.1 [100%,(M+H)⁺], 485.1 [30%, (M+Na)⁺]. HRMS (ESI+): m/z calcd for C₁₉H₂₂N₆O₄S₂(M+H)⁺ 463.1217, found 463.1214.

5-Methyl-N⁴-(3-[N-(cyclopropyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(RJ1-045-01)

A mixture of RJ1-046 (0.100 g, 0.295 mmol),4-(4-methyl-1-piperazinyl)aniline (0.056 g, 0.295 mmol), EtOH (2 mL) and4M HCl (3 drops) was allowed to react and worked up following the sameprocedure used for RJ1-014. The residue was then purified via flashchromatography eluting with DCM (with 6% MeOH) to provide the productRJ1-045-01 as a white, flaky solid (0.057 g, 39%). Mp: 201° C. (dec).HPLC 98% [t_(R)=14.5 min, gradient 5-95% MeOH and water (with 0.1% TFA),20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H, disappeared on D₂Oshake), 8.59 (s, 1H, disappeared on D₂O shake), 8.28 (brd, J=8.1 Hz,1H), 7.99 (s, 1H), 7.93 (d, J=2.2 Hz, 1H, disappeared on D₂O shake),7.89 (s, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.48-7.43 (m, 3H), 6.81 (d, J=9.0Hz, 2H), 3.04-2.99 (m, 4H), 2.47-2.39 (m, 4H), 2.21 (s, 3H), 2.11 (s,overlapping 3H and 1H), 0.53-0.35 (m, 4H). HPLC-MS (ESI+): m/z 494.2[10%, (M+H)⁺], 247.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): m/z 494.2 [100%,(M+H)⁺], 247.6 [15%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₁N₇O₂S(M+H)⁺ 494.2333, found 494.2332.

5-Chloro-N⁴-(3-Cyclopropylsulfonamido)phenyl-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(RJ1-051-01)

A mixture of RJ1-050 (0.500 g, 0.139 mmol),4-(4-methyl-1-piperazinyl)aniline (0.027 g, 0.139 mmol), EtOH (1 mL),and 4M HCl (2 drops) was allowed to react and worked up following thesame procedure used for RJ1-014. The residue was then purified via flashchromatography eluting with DCM (with 4% MeOH) to provide the productRJ1-051-01 as an off-white flaky solid (0.031 g, 43%). Mp: 178° C.(dec). HPLC 99.7% [t_(R)=12.3 min, 30% MeOH, 70% water (with 0.1% TFA),20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.80-9.65 (brs, 1H, disappeared onD₂O shake), 9.05-8.95 (brs, 1H, disappeared on D₂O shake), 8.85 (s, 1H,disappeared on D₂O shake), 8.07 (s, 1H), 7.51-7.35 (m, 4H), 7.26 (t,J=8.3 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 2H), 3.06-2.95(s, 4H), 2.69-2.55 (m, 1H), 2.47-2.35 (m, 4H), 2.19 (s, 3H), 0.98-0.80(m, 4H). HPLC-MS (ESI+): m/z 516.1 [30%, (M³⁷Cl+H)⁺], 514.2 [100%,(M³⁷Cl+H)⁺], 258.4 [40%, (M³⁷Cl+2H)²⁺], 257.6 [90%, (M³⁵Cl+2H)^(2+]).LC-MS (ESI+): m/z 516.2 [100%, (M³⁷Cl+H)⁺], 514.1 [35%, (M³⁵Cl+H)⁺].HRMS (ESI+): m/z calcd for C₂₄H₂₈ClN₇O₂S (M+H)⁺ 514.1787, found514.1801.

5-Chloro-N⁴-(3-[N-(cyclopropyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(RJ1-053-01)

A mixture of RJ1-052 (0.500 g, 0.139 mmol),4-(4-methyl-1-piperazinyl)aniline (0.027 g, 0.139 mmol), EtOH (1 mL),and 4M HCl (2 drops) was allowed to react and worked up following thesame procedure used for RJ1-014. The residue was then purified via flashchromatography eluting with DCM (with 4% MeOH) to provide the productRJ1-053-01 as a light beige solid (0.019 g, 26%). Mp: 205° C. (dec).HPLC 99% [t_(R)=6.7 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.15 (s, 1H, disappeared on D₂O shake),9.10 (s, 1H, disappeared on D₂O shake), 8.15-8.05 (brs, 1H, disappearedon D₂O shake), 8.13 (s, 1H), 7.98 (s, 1H), 7.95 (d, J=2.2 Hz, 1H),7.61-7.49 (m, 2H), 7.39 (d, J=8.9 Hz, 2H), 6.80 (d, J=8.9 Hz, 2H),3.06-2.95 (m, 4H), 2.47-2.39 (m, 4H), 2.21 (s, 3H), 2.16-2.07 (m, 1H),0.54-0.32 (m, 4H). HPLC-MS (ESI+): m/z 516.2 [30%, (M³⁷Cl+H)⁺], 514.2[100%, (M³⁵Cl+H)⁺], 258.4 [20%, (M³⁷Cl+2H)²⁺], 257.6 [20%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): m/z 516.2 [100%, (M³⁷Cl+H)⁺], 514.1 [40%,(M³⁵Cl+H)⁻]. (ESI+): m/z calcd for C₂₄H₂₈ClN₇O₂S (M+H)⁺ 514.1787, found514.1786.

5-Chloro-N⁴-[3-(1-methylethoxy)phenyl]-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(RJ1-057-01)

A mixture of RJ1-048 (0.500 g, 0.168 mmol),4-(4-methyl-1-piperazinyl)aniline (0.027 g, 0.168 mmol), EtOH (1 mL),and 4M HCl (2 drops) was allowed to react and worked up following thesame procedure as used for RJ1-014. The residue was then purified viaflash chromatography eluting with DCM (with 3-4% MeOH) to provide theproduct RJ1-057-01 as a foamy, champagne-colored solid (0.038 g, 50%).Mp: 135-137° C. HPLC 98% [t_(R)=10.4 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.09 (s, 1H, disappeared onD₂O shake), 8.64 (s, 1H, disappeared on D₂O shake), 8.07 (s, 1H), 7.43(d, J=9.0 Hz, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.23-7.13 (m, 2H), 6.76 (d,J=9.0 Hz, 2H), 6.65 (dd, J=8.2, 2.4 Hz, 1H), 4.52 (sept, J=6.0 Hz, 1H),3.05-2.94 (m, 4H), 2.46-2.37 (m, 4H), 2.19 (s, 3H), 1.23 (d, J=6.0 Hz,6H). HPLC-MS (ESI+): m/z 455.3 [20%, (M³⁷Cl+H)⁺], 453.2 [60%,(M³⁵Cl+H)⁺], 228.2 [20%, (M³⁷Cl+2H)²⁺], 227.2 [20%, (M³⁵Cl+2H)²⁺]. LC-MS(ESI+): m/z 455.2 [40%, (M³⁷Cl+H)⁺], 453.2 [100%, (M³⁵Cl+H)⁻]. HRMS(ESI+): m/z calcd for C₂₄H₂₉ClN₆O (M+H)⁺ 453.2164, found 453.2175.

5-Methyl-N⁴-[3-(1-methylethoxy)phenyl]-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamineRJ1-060-01)

A mixture of RJ1-058 (0.050 g, 0.180 mmol),4-(4-methyl-1-piperazinyl)aniline (0.034 g, 0.180 mol), EtOH (1 mL), and4M HCl (2 drops) was allowed to react and worked up following the sameprocedure as used for RJ1-014. The residue was then purified via flashchromatography eluting with DCM (with 4% MeOH) to provide the productRJ1-060-01 as a yellow-tan solid (0.028 g, 36%). Mp: 135-137° C. HPLC97% [t_(R)=8.3 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 8.70 (s, 1H, disappeared on D₂O shake), 8.08 (s,1H, disappeared on D₂O shake), 7.82 (s, 1H), 7.49 (d, J=9.0 Hz, 2H),7.35 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.2 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H),6.76 (d, J=9.0 Hz, 2H), 6.57 (dd, J=8.0, 2.1 Hz, 1H), 4.51 (sept, J=6.0Hz, 1H), 3.05-2.91 (m, 4H), 2.45-2.38 (m, 4H), 2.19 (s, 3H), 2.07 (s,3H), 1.23 (d, J=6.0 Hz, 6H). HPLC-MS (ESI+): m/z 433.3 [20%, (M+H)⁺],217.3 [100%, (M+2H)²⁺]. LC-MS (ESI+): m/z 217.1 [10%, (M+2H)²⁺], 433.3[100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₂N₆O (M+H)⁺ 433.2710,found 433.2708.

5-Carboethoxy-N⁴-(4-Chloro-3-methoxyphenyl)-M-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(RJ1-064-01)

A mixture of RJ1-061 (0.200 g, 0.584 mmol),4-(4-methyl-1-piperazinyl)aniline (0.112 g, 0.584 mmol), EtOH (4 mL),and 4M HCl (8 drops) and was reacted following the same procedure asused for RJ1-014. The residue was then purified via flash chromatographychromatography eluting with DCM (with 4% MeOH) to provide the productRJ1-064-01 as an off-white solid (0.116 g, 40%). Mp: 203° C. (dec). HPLC97% [t_(R)=8.0 min, 60% MeOH, 40% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 10.12 (s, 1H, 50% reduced on D₂O shake), 9.37 (s,1H, disappeared on D₂O shake), 8.68 (s, 1H), 7.30-7.26 (d, J=9.0 Hz, 2H,overlapping s, 1H), 7.28 (d, J=8.5 Hz, 2H), 6.82 (d, J=9.0 Hz, 2H), 4.32(q, J=7.0 Hz, 2H), 3.71 (s, 3H), 3.13-3.06 (m, 4H), 2.50-2.44 (m, 4H,partly overlapped by residual DMSO solvent signal), 2.23 (s, 3H), 1.34(t, J=7.0 Hz, 3H). HPLC-MS (ESI+): m/z 499.2 [30%, (M³⁷Cl+H)⁺], 497.2[100%, (M³⁵Cl+H)⁺], 250.2 [30%, (M³⁷Cl+2H)²⁺], 249.2 [60%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): m/z 249.1 [10%, (M³⁵Cl+2H)²⁺], 499.2 [40%,(M³⁷Cl+H)⁺], 497.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₅H₂₉ClN₆O₃ (M+H)⁺ 497.2062, found 497.2063.

5-Carboethoxy-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(RJ1-066-01)

A mixture of RJ1-063-01 (0.150 g, 0.363 mmol),4-(4-methyl-1-piperazinyl)aniline (0.069 g, 0.363 mmol), EtOH (3 mL),and 4M HCl (6 drops) and was reacted following the same procedure usedfor RJ1-014. The residue was then purified via flash chromatographyeluting with DCM (with 4% MeOH) to provide the product RJ1-066-01 as anoff-white solid (0.093 g, 45%). Mp: 202° C. (dec). HPLC 95% [t_(R)=6.2min, 60% MeOH, 40% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz,DMSO-d₆): δ 10.27 (s, 1H, 75% reduced on D₂O shake), 9.38 (s, 1H,disappeared on D₂O shake), 8.70 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.90(s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.8Hz, 2H), 7.22 (s, 1H), 6.85 (d, J=8.8 Hz, 2H), 4.34 (q, J=6.9 Hz, 2H),3.12-3.06 (m, 4H,), 2.48-2.42 (m, 4H, partly overlapped by residual DMSOsolvent signal), 2.23 (s, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.13 (s, 9H).HPLC-MS (ESI+): m/z 568.3 [80%, (M+H)⁺], 284.7 [100%, (M+2H)²⁺]. LC-MS(ESI+): m/z 284.6 [10%, (M+2H)²⁺], 568.3 [100%, (M+H)⁺]. HRMS (ESI+):m/z calcd for C₂₈H₃₇N₇O₄S (M+H)⁺ 568.2701, found 568.2677.

5-Methyl-N⁴-(3,4,5-trimethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-063-01)

This was obtained as a light brown solid (30 mg, 40%) from SG2-050 (50mg) and 4-(4-methylpiperazino)aniline (31 mg) using the general methodx. Mp: 248° C. (dec). HPLC: 99% [t_(R)=7.6 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (s, 1H,disappeared on D₂O shake), 8.13 (s, 1H, disappeared on D₂O shake), 7.81(s, 1H), 7.46 (d, J=9.0 Hz, 2H), 6.97 (s, 2H), 6.73 (d, J=9.0 Hz, 2H),3.65 (s, 6H), 3.63 (s, 3H), 3.01-2.94 (m, 4H), 2.45-2.39 (m, 4H), 2.19(s, 3H), 2.05 (s, 3H). HPLC-MS (ESI+): m/z 465.3 [20%, (M+H)⁺], 233.2[80%, (M+2H)²⁺]. LC-MS (ESI+): 465.2 [100%, (M+H)⁺], 233.1 [20%,(M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₂N₆O₃ (M+H)⁺ 465.2609, found465.2601.

5-Methyl-N⁴-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-064-01)

This was obtained as a brown oil (23 mg, 30%) from SG2-051 (50 mg) and4-(4-methylpiperazino)aniline (34 mg) using the general method x. HPLC:98% [t_(R)=8.3 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 8.65 (s, 1H, disappeared on D₂O shake), 8.01 (s,1H, disappeared on D₂O shake), 7.76 (s, 1H), 7.47 (d, J=9.0 Hz, 2H),7.25 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.7, 2.4 Hz, 1H), 6.77 (d, J=8.7 Hz,1H), 6.76 (d, J=9.0 Hz, 2H), 4.25-4.19 (m, 4H), 3.01-2.96 (m, 4H),2.45-2.41 (m, 4H), 2.19 (s, 3H), 2.03 (s, 3H). HPLC-MS (ESI+): m/z 433.3(M+H, 20%)⁺, 217.1 [100%, (M+2H)²⁻]. LC-MS (ESI+): 433.2 [100%, (M+H)⁻],217.2 [20%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₄H₂₈N₆O₂ (M+H)⁺433.2347, found 433.2341.

5-Methyl-N⁴-(benzo[d][1,3]dioxol-5-yl)-M-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-065-01)

This was obtained as a red solid (25 mg, 32%) from SG2-052 (50 mg) and4-(4-methylpiperazino)aniline (36 mg) using the general method x. Mp:236° C. (dec). HPLC: 99% [t_(R)=8.8 min, 35% MeOH, 65% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.67 (s, 1H, disappeared onD₂O shake), 8.08 (s, 1H, disappeared on D₂O shake), 7.77 (s, 1H), 7.46(d, J=9.0 Hz, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.4, 2.0 Hz, 1H),6.84 (d, J=8.4 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 5.99 (s, 2H), 3.04-2.96(m, 4H), 2.45-2.40 (m, 4H), 2.19 (s, 3H), 2.04 (s, 3H). HPLC-MS (ESI+):m/z 419.2 [20%, (M+H)⁺], 210.2 [100%, (M+2H)²⁺]. LC-MS (ESI+): 419.2[100%, (M+H)⁺], 210.1 [10%, (M+2H)^(2′) ]. HRMS (ESI+): m/z calcd forC₂₃H₂₆N₆O₂ (M+H) 419.2190, found 419.2193.

5-Chloro-N⁴-(4-chloro-3,5-dimethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-069-01)

This was obtained as an off-white solid (46 mg, 63%) from SG2-066 (50mg) and 4-(4-methylpiperazino)aniline (29 mg) using the general methodx. Mp: 231° C. (dec). HPLC: 96% [t_(R)=6.6 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.10 (s, 1H,disappeared on D₂O shake), 8.80 (s, 1H, disappeared on D₂O shake), 8.10(s, 1H), 7.38 (d, J=8.9 Hz, 2H), 7.14 (s, 2H), 6.75 (d, J=8.9 Hz, 2H),3.68 (s, 6H), 3.04-2.97 (m, 4H), 2.45-2.39 (m, 4H), 2.19 (s, 3H).HPLC-MS (ESI+): m/z 491.2 [60%, (M³⁵Cl³⁷Cl+H)⁻], 489.2 (90%,M³⁵Cl³⁵Cl+H)⁺], 246.1 [70%, (M³⁵Cl³⁷Cl+2H)²⁺], 245.1 [100%,M³⁵Cl³⁵Cl+2H)²⁺]. LC-MS (ESI+): 491.2 [60%, (M³⁵Cl³⁷Cl+H)⁺], 489.2[100%, (M³⁵Cl³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₃H₂₆Cl₂N₆₀₂ (M+H)⁺489.1567, found 489.1561.

5-Methyl-N⁴-(4-chloro-3,5-dimethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-070-01)

This was obtained as a light green solid (40 mg, 53%) from SG2-067 (50mg) and 4-(4-methylpiperazino)aniline (31 mg) using the general methodx. Mp: 223° C. (dec). HPLC: 98% [t_(R)=11.3 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H,disappeared on D₂O shake), 8.27 (s, 1H, disappeared on D₂O shake), 7.86(s, 1H), 7.43 (d, J=9.1 Hz, 2H), 7.18 (s, 2H), 6.75 (d, J=9.1 Hz, 2H),3.69 (s, 6H), 3.02-2.96 (m, 4H), 2.45-2.39 (m, 4H), 2.19 (s, 3H), 2.08(s, 3H). HPLC-MS (ESI+): m/z 469.2 [20%, (M³⁵Cl+H)⁺], 235.2 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 471.2 [30%, (M³⁵Cl+H)⁺], 469.2 [100%,(M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₄H₂₉ClN₆O₂ (M+H)⁺ 469.2113,found 469.2114.

6-Methyl-N⁴-(4-chloro-3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-071-01)

This was obtained as a yellow oil (32 mg, 42%) from SG2-053 (50 mg) and4-(4-methylpiperazino)aniline (34 mg) using the general method x. HPLC:95% [t_(R)=7.7 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.28 (s, 1H, disappeared on D₂O shake), 8.86 (s,1H, disappeared on D₂O shake), 7.47 (d, J=9.0 Hz, 2H), 7.40 (d, J=2.1Hz, 1H), 7.34-7.26 (m, 1H), 7.23 (d, J=8.6 Hz, 1H), 6.82 (d, J=9.0 Hz,2H), 6.00 (s, 1H), 3.67 (s, 3H), 3.06-2.99 (m, 4H), 2.45-2.40 (m, 4H),2.20 (s, 3H), 2.17 (s, 3H). HPLC-MS (ESI+): m/z 439.2 [30%, (M³⁵Cl+H)⁺],221.2 [30%, (M³⁷Cl+2H)²⁺], 220.2 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+):441.2 [30%, (M³⁷Cl+H)⁺], 439.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₃H₂₇ClN₆O (M+H) 439.2008, found 439.2009.

5-Methyl-N⁴-(4-chloro-2,5-dimethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-072-01)

This was obtained as an off-white solid (29 mg, 39%) from SG2-068 (50mg) and 4-(4-methylpiperazino)aniline (31 mg) using the general methodx. Mp: 252° C. (dec). HPLC: 94% [t_(R)=13.5 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.69 (s, 1H,disappeared on D₂O shake), 7.83 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H,disappeared on D₂O shake), 7.35 (d, J=9.0 Hz, 2H), 7.16 (s, 1H), 6.72(d, J=9.0 Hz, 2H), 3.77 (s, 3H), 3.62 (s, 3H), 3.02-2.95 (m, 4H),2.45-2.40 (m, 4H), 2.19 (s, 3H), 2.05 (s, 3H). HPLC-MS (ESI+): m/z 469.2[20%, (M³⁵Cl+H)⁺], 236.2 [20%, (M³⁷Cl+2H)²⁺], 235.2 [60%, (M³⁵Cl+2H)²⁺].LC-MS (ESI+): 469.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₄H₂₉ClN₆O₂ (M+H)⁺ 469.2113, found 469.2115.

5-Methyl-N⁴-(4-chloro-3-methoxyphenyl)-N²-[4-(piperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-081-01)

This was obtained as a light yellow solid (26 mg, 35%) from SG1-173-01(50 mg) and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (49 mg)using the general method x. Mp: 245° C. (dec). HPLC: 98% [t_(R)=12.5min, 35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz,DMSO-d₆): δ 8.73 (s, 1H, disappeared on D₂O shake), 8.28 (s, 1H,disappeared on D₂O shake), 7.85 (s, 1H), 7.48 (d, J=2.0 Hz, 1H),7.46-7.40 (m, 3H), 7.26 (d, J=8.6 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 3.71(s, 3H), 2.95-2.87 (m, 4H), 2.83-2.77 (m, 4H), 2.07 (s, 3H). HPLC-MS(ESI+): m/z 425.2 [25%, (M³⁵Cl+H)⁺], 214.2 [40%, (M³⁷Cl+2H)²⁺], 213.2[100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 427.2 [30%, (M³⁷Cl+H)⁺], 425.2[100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₂H₂₅ClN₆O (M+H)⁺425.1851, found 425.1861.

5-Chloro-N⁴-[3-(N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-085-01)

This was obtained as a light yellow solid (31 mg, 44%) from SG2-082 (50mg) and 4-(4-methylpiperazino)aniline (24 mg) using the general methodx. Mp: 258° C. (dec). HPLC: 93% [t_(R)=6.7 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (s, 2H,disappeared on D₂O shake), 8.12 (s, 1H), 8.07 (brs, 1H), 8.00 (br d,J=7.0 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.43-7.34(m, 3H; 1H disappeared on D₂O shake), 6.79 (d, J=8.9 Hz, 2H), 4.78 (t,J=5.8 Hz, 1H, disappeared on D₂O shake), 3.19 (d, J=5.8 Hz, 2H),3.07-2.96 (m, 4H), 2.46-2.37 (m, 4H), 2.19 (s, 3H), 1.01 (s, 6H).HPLC-MS (ESI+): m/z 548.3 [40%, (M³⁷Cl+H)⁺], 546.3 [100%, (M³⁵Cl+H)⁺],274.6 [50%, (M³⁷Cl+2H)²⁺], 273.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+):548.2 [40%, (M³⁷Cl+H)⁺], 546.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₅H₃₂ClN₇O₃S (M+H)⁺ 546.2049, found 546.2056.

5-Methyl-N⁴-[3-(N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl)phenyl]-NM-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-087-01)

This was obtained as a yellow solid (15 mg, 21%) from SG2-083-02 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 273° C. (dec). HPLC: 93% [t_(R)=11.7 min, 30% MeOH, 70% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.70 (s, 1H,disappeared on D₂O shake), 8.50 (s, 1H, disappeared on D₂O shake), 8.12(s, 2H), 7.87 (s, 1H), 7.48-7.43 (m, 4H), 7.38 (s, 1H, disappeared onD₂O shake), 6.80 (d, J=9.1 Hz, 2H), 4.78 (t, J=5.9 Hz, 1H, disappearedon D₂O shake), 3.20 (d, J=5.9 Hz, 2H), 3.05-2.97 (m, 4H), 2.44-2.40 (m,4H), 2.19 (s, 3H), 2.09 (s, 3H), 1.02 (s, 6H). HPLC-MS (ESI+): m/z 526.2[60%, (M+H)⁺], 263.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 526.3 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₅N₇O₃S (M+H)⁺ 526.2595, found526.2611.

5,6-Dimethyl-N⁴-[3-(N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-088-01)

This was obtained as a yellow oil (14 mg, 20%) from SG2-084-02 (50 mg)and 4-(4-methylpiperazino)aniline (25 mg) using the general method x.HPLC: 94% [t_(R)=7.7 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 8.65 (s, 1H, disappeared on D₂O shake),8.43 (s, 1H, disappeared on D₂O shake), 8.07-7.97 (m, 2H), 7.49-7.41 (m,4H), 7.34 (s, 1H, disappeared on D₂O shake), 6.77 (d, J=9.1 Hz, 2H),4.77 (t, J=5.9 Hz, 1H, disappeared on D₂O shake), 3.19 (d, J=5.9 Hz,2H), 3.02-2.94 (m, 4H), 2.44-2.38 (m, 4H), 2.25 (s, 3H), 2.19 (s, 3H),2.09 (s, 3H), 1.01 (s, 6H). HPLC-MS (ESI+): m/z 540.4 [20%, (M+H)⁺],270.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 540.3 [100%, (M+H)⁺], 270.6 [20%,(M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₇N₇O₃S (M+H)⁺ 540.2751, found540.2746.

5-Chloro-N⁴-[3,5-dimethoxyphenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-070)

This was obtained as a white solid (44 mg, 58%) from MA1-069 (50 mg) and4-(4-methylpiperazino)aniline (32 mg) using the general method x. Mp:201° C. (dec). HPLC: 100% [t_(R)=14.9 min, 35% MeOH, 65% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (s, 1H,disappeared on D₂O shake), 8.62 (s, 1H, disappeared on D₂O shake), 8.07(s, 1H), 7.44 (d, J=9.0 Hz, 2H), 6.91 (brd, J=2.0 Hz, 2H), 6.76 (d,J=9.0 Hz, 2H), 6.25 (t, J=2.0 Hz, 1H), 3.67 (s, 6H), 3.03-2.98 (m, 4H),2.45-2.40 (m, 4H), 2.20 (s, 3H). HPLC-MS (ESI+): m/z 457.2 [25%,(M³⁷Cl+H)⁺], m/z 455.2 [75%, (M³⁵Cl+H)], m/z 229.2 [38%, (M³⁷Cl+2H)²⁺],m/z 228.2 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 457.2 [30%, (M³⁷Cl+H)⁺],455.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₃H₂₇ClN₆O₂ (M+H)⁺455.1957, found 455.1942.

N⁴-[4-Chloro-3-methoxyphenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-094B)

This was obtained as a white solid (47 mg, 44%) from MA1-092 (100 mg)and 4-(4-methylpiperazino)aniline (48 mg) using the general method x.Mp: 231° C. (dec). HPLC: 92% [t_(R)=8.4 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.42 (s, 1H,disappeared on D₂O shake), 8.91 (s, 1H, disappeared on D₂O shake), 7.98(d, J=5.7 Hz, 1H), 7.48 (d, J=9.0 Hz, 2H), 7.44 (d, J=2.2 Hz, 1H), 7.35(brd, J=8.6 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 6.86 (d, J=9.0 Hz, 2H),6.15 (d, J=5.7 Hz, 1H), 3.71 (s, 3H), 3.13-3.03 (m, 4H), 2.61-2.54 (m,4H), 2.30 (s, 3H). HPLC-MS (ESI+): m/z 425.2 [25%, (M³⁵Cl+2H)⁺], 214.2[38%, (M³⁷Cl+2H)²⁺], 213.2 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 427.2[30%, (M³⁷Cl+H)⁺], 425.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₂H₂₅ClN₆O (M+H)⁺ 425.1851, found 425.1846.

5-Chloro-N⁴-[4-chloro-3-isopropoxyphenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-096-1)

This was obtained as a gold-colored solid (38 mg, 52%) from MA1-088 (50mg) and 4-(4-methylpiperazino)aniline (29 mg) using the general methodx. Mp: 212° C. (dec). HPLC: 96% [t_(R)=6.1 min, 50% MeOH, 50% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.09 (s, 1H,disappeared on D₂O shake), 8.79 (s, 1H, disappeared on D₂O shake), 8.09(s, 1H), 7.45-7.34 (m, 4H), 7.29 (d, J=8.6 Hz, 1H), 6.78 (d, J=9.1 Hz,2H), 4.47 (sextet, 6.0 Hz, 1H), 3.04-2.98 (m, 4H), 2.44-2.39 (m, 4H),2.19 (s, 3H), 1.24 (d, J=6.0 Hz, 6H). HPLC-MS (ESI+): m/z 489.2 [60%,(M³⁵Cl³⁷Cl+2H)²⁺], 487.2 [95%, (M³⁵Cl³⁷Cl+2H)²⁺], 245.1 [72%(MCl³⁵Cl³⁷+2H)²⁺], 244.2 [100%, (MCl³⁵Cl³⁵+2H)²⁺]. LC-MS (ESI+): 489.2[100%, (M³⁵Cl³⁷Cl+H)⁺], 487.2 [100%, (M³⁵Cl³⁵Cl+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₄H₂₈Cl₂N₆O (M+H)⁺ 487.1774, found 487.1782.

5-Propyl-N⁴-[3-methoxy-4-chlorophenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-096-2)

This was obtained as a white solid (41 mg, 55%) from MA1-072 (50 mg) and4-(4-methylpiperazino)aniline (31 mg) using the general method x. Mp:250° C. (dec). HPLC: 96% [t_(R)=18.9 min, 40% MeOH, 60% water (with 0.1%TFA), 30 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.76 (s, 1H, disappeared onD₂O shake), 8.31 (s, 1H, disappeared on D₂O shake), 7.85 (s, 1H),7.49-7.42 (m, 3H), 7.40-7.35 (m, 1H), 7.28 (d, J=8.6 Hz, 1H), 6.77 (d,J=9.0 Hz, 2H), 3.72 (s, 3H), 3.05-2.96 (m, 4H), 2.52-2.47 (m, 2H,overlapped with the residual DMSO signal) 2.47-2.39 (m, 4H), 2.21 (s,3H), 1.54 (sextet, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H). HPLC-MS(ESI+): m/z 467.3 [30%, (M³⁵Cl+H)⁺], 235.1 [40%, (M³⁷Cl+2H)²⁺], 234.2[100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 469.2 [30%, (M³⁷Cl+2H)²⁺], 467.2[100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₁ClN₆O (M+H)⁺467.2321, found 467.2302.

5-Methylethyl-N⁴-[3-methoxy-4-chlorophenyl]-M-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA1-096-3)

This was obtained as a white solid (19 mg, 26%) from MA1-073 (50 mg) and4-(4-methylpiperazino)aniline (36 mg) using the general method x. Mp:212° C. (dec). HPLC: 99% [t_(R)=15.2 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H, disappeared onD₂O shake), 8.33 (s, 1H, disappeared on D₂O shake), 7.95 (s, 1H),7.45-7.41 (m, 3H), 7.36 (d, J=8.6, 2.0 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H),6.75 (d, J=9.1 Hz, 2H), 3.69 (s, 3H), 3.14 (septet, J=6.8 Hz, 1H),3.03-2.95 (m, 4H), 2.46-2.40 (m, 4H), 2.20 (s, 3H), 1.19 (d, J=6.8 Hz,6H). HPLC-MS (ESI+): m/z 467.3 [20%, (M³⁵Cl+H)⁺], 235.2 [30%,(M³⁷Cl+2H)²⁺], 234.3 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 469.2 [35%,(M³⁵Cl+H)⁺], 467.2 [100%, (M³⁵Cl+H)⁺], 234.1 [25%, (MCl³⁵+2H)²⁺]. HRMS(ESI+): m/z calcd for C₂₅H₃₁ClN₆O (M+H)⁺ 467.2321 found 467.2344.

5-Bromo-N⁴-[4-chloro-3-methoxyphenyl]-N²-[4-(piperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-012)

Trifluoroacetic acid (4 mL of freshly prepared 50% solution in DCM) wasadded to MA2-010 (280 mg) in a 20 mL microwave vial equipped with amagnetic stirrer bar. The reaction mixture was stirred at roomtemperature for 30 h at which point HPLC-MS confirmed the completeconsumption of starting material. The mixture was diluted with DCM (100mL) and water (30 mL). Triethylamine (ca. 5.5 mL) was added slowly tothis mixture until a pH was 11. The mixture was transferred to aseparatory funnel and separated. The aqueous layer was further extractedwith DCM (50 mL). Combined organic layers were evaporated, dried(Na₂SO₄) and evaporated to provide the title compound (190 mg, 83%) as adark gray to black solid. Mp: 268° C. (dec). HPLC: 98% [t_(R)=11.6 min,40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆):δ 9.17 (s, 1H, disappeared on D₂O shake), 8.62 (s, 1H, disappeared onD₂O shake), 8.19 (s, 1H), 7.44-7.40 (m, 3H), 7.33 (s, 2H), 6.80 (d,J=9.0 Hz, 2H), 3.72 (s, 3H), 3.10-3.00 (m, 8H). HPLC-MS (ESI+): m/z491.1 [38%, (M⁸¹Br+H)⁺], 489.1 [45%, (M⁷⁹Br+H)⁻], 245.2 [40%,(M⁷⁹Br+2H)²⁺]. LC-MS (ESI+): 491.1 [100%, (M⁸¹Br+H)⁺], 489.1 [75%,(M⁷⁹Br+H)⁺. HRMS (ESI+): m/z calcd for C₂₁H₂₂BrClN₆O (M+H)⁺ 489.0800,found 489.0793.

5-Methyl-N⁴-[3-(1,1-dimethylethyl)sulfonamidophenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-014)

This was obtained as a green solid (41 mg, 48%) from MA2-008 (60 mg) and4-(4-methylpiperazino)aniline (32 mg) using the general method x. Mp:173° C. (dec). HPLC: 99% [t_(R)=5.9 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.56 (s, 1H, disappeared onD₂O shake), 8.57 (s, 1H, disappeared on D₂O shake), 8.29 (s, 1H,disappeared on D₂O shake), 7.82 (s, 1H), 7.54 (s, 1H), 7.51-7.43 (m,3H), 7.19 (t, J=8.2 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.78 (d, J=8.7 Hz,2H), 3.08-2.97 (m, 4H), 2.53-2.47 (m, 4H, appeared from the solventsignal on D₂O shake), 2.30 (brs, 3H), 2.06 (s, 3H), 1.26 (s, 9H).HPLC-MS (ESI+): m/z 510.3 [15%, (M+H)⁺], 255.7 [100%, (M+2H)²⁺]. LC-MS(ESI+): 510.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₅N₇O₂S(M+H)⁺ 510.2646, found 510.2637.

5-Chloro-N⁴-(4-chloro-3-ethoxyphenyl)-M-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-024-1)

This was obtained as a white solid (45 mg, 62%) from MA2-016-1 (50 mg)and 4-(4-methylpiperazino)aniline (30 mg) using the general method x.Mp: 228° C. (dec). HPLC: 99% [t_(R)=16.3 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.11 (s, 1H,disappeared on D₂O shake), 8.81 (s, 1H, disappeared on D₂O shake), 8.10(s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.41-7.33 (m, 3H), 7.31 (d, J=8.6 Hz,1H), 6.79 (d, J=9.0 Hz, 2H), 3.97-3.87 (m, 2H), 3.08-3.00 (m, 4H),2.48-2.42 (m, 4H), 2.21 (s, 3H), 1.30 (t, J=6.9 Hz, 3H). HPLC-MS (ESI+):m/z 475.3 [65%, (M³⁵Cl³⁷Cl+H)⁺], 473.2 (100%, M³⁵Cl³⁵Cl+H)⁺], 238.2[53%, (M³⁷Cl³⁵Cl+2H)²⁺], 237.2 [83%, (M³⁵Cl³⁵Cl+2H)²⁺]. LC-MS (ESI+):475.2 [60%, (M³⁵Cl³⁷Cl+H)⁺], 473.2 [100%, (M³⁵Cl³⁵Cl+H)⁺]. HRMS (ESI+):m/z calcd for C₂₃H₂₆Cl₂N₆₀ (M+H)⁺ 473.1618, found 473.1629.

5-Methyl-N⁴-(4-chloro-3-ethoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-024-2)

This was obtained as a white solid (16 mg, 22%) from MA2-016-2 (50 mg)and 4-(4-methylpiperazino)aniline (32 mg) using the general method x.Mp: 214° C. (dec). HPLC: 97% [t_(R)=12.7 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H,disappeared on D₂O shake), 8.25 (s, 1H, disappeared on D₂O shake), 7.84(s, 1H), 7.48-7.36 (m, 4H), 7.26 (d, J=8.6 Hz, 1H), 6.77 (d, J=9.1 Hz,2H), 3.91 (q, J=6.9 Hz, 2H), 3.04-2.97 (m, 4H), 2.46-2.40 (m, 4H), 2.20(s, 3H), 2.07 (s, 3H), 1.28 (t, J=6.9 Hz, 3H). HPLC-MS (ESI+): m/z 453.2[30%, (M³⁵Cl+H)⁺], 228.2 [38%, (M³⁷Cl+2H)²⁺], 227.2 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 455.2 [30%, (M³⁷Cl+H)⁺], 453.2 [100%,(M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₄H₂₉ClN₆O (M+H)⁺ 453.2164,found 453.2150.

N-(4-Chloro-3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]quinazoline-2,4-diamine(MA2-032)

This was obtained as a green solid (37 mg, 50%) from MA2-030 (50 mg) and4-(4-methylpiperazino)aniline (29 mg) using the general method x. Mp:188° C. (dec). HPLC: 96% [t_(R)=4.9 min, 50% MeOH, 50% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.58 (s, 1H, disappeared onD₂O shake), 8.97 (s, 1H, disappeared on D₂O shake), 8.28 (dd, J=8.2, 0.8Hz, 1H), 7.73-7.62 (m, 5H), 7.44 (d, J=8.4 Hz, 1H), 7.36 (d, J=9.1 Hz,1H), 7.25 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 6.87 (d, J=9.0 Hz, 2H), 3.82(s, 3H), 3.12-3.04 (m, 4H), 2.59-2.50 (m, 4H), 2.28 (s, 3H). HPLC-MS(ESI+): m/z 477.3 [15%, (M³⁷Cl+H)⁺], 475.3 [40%, (M³⁵C+H)⁺], 238.3[100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 477.2 [30%, (M³⁷Cl+H)⁺], 475.2[100%, (M³⁵C+H)⁺], 238.1 [30%, (M³⁵Cl+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₆H₂₇ClN₆O (M+H)⁺ 475.2008, found 475.2023.

5-Methyl-N⁴-[4-chloro-3-(1-methylethoxy)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-031)

This was obtained as a gray solid (7 mg, 9%) from MA1-090 (50 mg) and4-(4-methylpiperazino)aniline (31 mg) using the general method x. Mp:264° C. (dec). HPLC: 97% [t_(R)=9.1 min, 45% MeOH, 55% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (s, 1H, disappeared onD₂O shake), 8.25 (s, 1H, disappeared on D₂O shake), 7.87 (s, 1H),7.53-7.42 (m, 4H), 7.28 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 4.46(septet, J=6.0 Hz, 1H), 3.20-3.05 (brs, 4H), 2.86-2.71 (brs, 4H), 2.45(s, 3H), 2.09 (s, 3H), 1.26 (d, J=6.0 Hz, 6H). HPLC-MS (ESI+): m/z 467.2[30%, (M³⁵Cl+H)⁺], 235.0 [40%, (M³⁷Cl+2H)²⁺], 234.3 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 469.2 [30%, (M³⁷Cl+H)⁺], 467.2 [100%,(M³⁵Cl+H)⁻]. HRMS (ESI+): m/z calcd for C₂₅H₃₁ClN₆O (M+H)⁺ 467.2321,found 467.2329.

N⁴-([3-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]quinazoline-2,4-diamine(MA2-034)

This was obtained as a green solid (11 mg, 16%) from MA2-033 (50 mg) and4-(4-methylpiperazino)aniline (24 mg) using the general method x. Mp:229° C. (dec). HPLC 99% [t_(R)=13.4 min, 45% MeOH, 55% water (with 0.1%TFA), 20 min]; ¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H, disappeared onD₂O shake), 8.92 (s, 1H, disappeared on D₂O shake), 8.44-8.37 (m, 2H),8.36-8.28 (1H, s, disappeared on D₂O shake), 7.74-7.63 (m, 4H),7.56-7.53 (m, 2H), 7.45 (d, J=8.5 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 6.89(d, J=9.1 Hz, 2H), 3.12-3.03 (m, 4H), 2.48-2.44 (m, 4H, overlapped byresidual DMSO signal), 2.23 (s, 3H), 1.15 (s, 9H). HPLC-MS (ESI+) m/z273.7 [100%, (M+2H)²⁺], 546.2 [40%, (M+H)⁺]; LC-MS 546.3 [100%, (M+H)⁺],273.6 [10%, (M+2H)²⁺], 245.6 [40%, (M-tBu+2H)²⁺]; HRMS (ESI+) m/zcalculated for C₂₉H₃₅N₇O₂S (M+H)⁺ 546.2646, found 546.2626.

5-Methyl-N⁴-(3-methylsulfonamidophenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-046)

This was obtained as a white solid (42 mg, 56%) from MA2-035 (50 mg) and4-(4-methylpiperazino)aniline (30 mg) using the general method x. Mp:198° C. (dec). HPLC: 96% [t_(R)=4.4 min, 35% MeOH, 65% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.69 (brs, 1H, disappearedon D₂O shake), 8.61 (s, 1H, disappeared on D₂O shake), 8.31 (s, 1H,disappeared on D₂O shake), 7.85 (s, 1H), 7.55 (d, J=8.1 Hz, 1H),7.51-7.44 (m, 3H), 7.25 (t, J=8.1 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.79(d, J=8.9 Hz, 2H), 3.05-2.99 (m, 4H), 2.99 (s, 3H), 2.47-2.40 (m, 4H),2.21 (s, 3H), 2.09 (s, 3H). HPLC-MS (ESI+): m/z 468.3 [20%, (M+H)⁺],234.8 [100%, (M+2H)²⁺]. LC-MS (ESI+): 468.2 [100%, (M+H)⁺]. HRMS (ESI+):m/z calcd for C₂₃H₂₉N₇O₂S (M+H) 468.2176, found 468.2161.

N-(3-Cyclopropylsulfonamido)phenyl-N²-[4-(4-methylpiperazin-1-yl)phenyl]quinazoline-2,4-diamine(MA2-047)

This was obtained as a green solid (26 mg, 38%) from MA2-038 (50 mg) and4-(4-methylpiperazino)aniline (26 mg) using the general method x. Mp:294° C. (dec). HPLC: 99% [1R=10.9 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H, disappeared onD₂O shake), 9.59 (s, 1H, disappeared on D₂O shake), 8.73 (s, 1H,disappeared on D₂O shake), 8.35 (d, J=7.7 Hz, 1H), 7.81-7.74 (brd, 2H),7.66 (brd, J=8.2 Hz, 2H), 7.62 (t, J=7.7 Hz, 1H), 7.41 (d, J=8.3 Hz,1H), 7.30 (t, J=8.3 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 6.98 (d, J=7.7 Hz,1H), 6.85 (d, J=9.1 Hz, 2H), 3.10-2.98 (m, 4H), 2.72-2.59 (m, 1H),2.48-2.44 (m, 4H, appeared from the solvent signal on D₂O shake), 2.22(s, 3H), 1.04-0.86 (m, 4H). HPLC-MS (ESI+): m/z 530.2 [40%, (M+H)⁺],265.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 530.2 [100%, (M+H)⁺], 265.6 [100%,(M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₁N₇O₂S (M+H)⁺ 530.2333, found530.2316.

5-Methyl-N⁴-[3-(2,2-dimethylpropanamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-052-1)

This was obtained as a beige solid (33 mg, 45%) from MA2-042-1 (50 mg)and 4-(4-methylpiperazino)aniline (30 mg) using the general method x.Mp: 273° C. (dec). HPLC: 99% [t_(R)=6.6 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.70 (s,1H, disappeared on D₂O shake), 8.26 (s, 1H, disappeared on D₂O shake),7.85 (t, J=1.9 Hz, 1H), 7.83 (s, 1H), 7.49 (d, J=9.0 Hz, 2H), 7.42 (d,J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 6.72 (d,J=9.0 Hz, 2H), 3.03-2.96 (m, 4H), 2.49-2.45 (m, 4H), 2.24 (s, 3H), 2.08(s, 3H), 1.21 (s, 9H). HPLC-MS (ESI+): m/z 474.3 [30%, (M+H)⁻], 237.8[100%, (M+2H)²⁺]. LC-MS (ESI+): 474.3 [100%, (M+H)⁺], 273.7 [35%,(M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₅N₇O (M+H)⁺ 474.2976, found474.2974.

5-Methyl-N⁴-[3-(2-methylpropanamido)phenyl]-N²a-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-052-2)

This was obtained as a beige solid (32 mg, 43%) from MA2-042-2 (47 mg)and 4-(4-methylpiperazino)aniline (30 mg) using the general method x.Mp: 259° C. (dec). HPLC: 99% [t_(R)=5.1 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.84 (s, 1H), 8.75 (s,1H, disappeared on D₂O shake), 8.27 (s, 1H, disappeared on D₂O shake),7.87 (s, 1H), 7.82 (s, 1H), 7.52 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.0 Hz,1H), 7.31 (d, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.75 (d, J=9.0 Hz,2H), 3.19-3.04 (brs, 4H), 2.95-2.80 (brs, 4H), 2.59 (septet, J=6.8 Hz,6H), 2.52 (s, 3H), 2.06 (s, 3H), 1.06 (d, J=6.8 Hz, 6H). HPLC-MS (ESI+):m/z 460.3 [20%, (M+H)⁺], 230.8 [100%0, (M+2H)²⁺]. LC-MS (ESI+): 460.3[100%0, (M+H)⁺], 230.6 [15%0, (M+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₆H₃₃N₇O (M+H)⁺ 460.2819, found 460.2805.

5-Methyl-N⁴-[3-(cyclopropylcarboxamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-052-3)

This was obtained as a beige solid (27 mg, 38%) from MA2-042-3 (47 mg)and 4-(4-methylpiperazino)aniline (30 mg) using the general method x.Mp: 227° C. (dec). HPLC: 99% [t_(R)=4.3 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 10.14 (s, 1H, 50%reduced on D₂O shake), 8.66 (s, 1H, disappeared on D₂O shake), 8.24 (s,1H, disappeared on D₂O shake), 7.84 (s, 1H), 7.81 (s, 1H), 7.48 (d,J=9.1 Hz, 2H), 7.35-7.27 (m, 2H), 7.20 (t, J=8.0 Hz, 1H), 6.72 (d, J=9.1Hz, 2H), 3.01-2.94 (m, 4H), 2.47-2.40 (m, 4H), 2.22-2.18 (brs, 3H), 2.06(s, 3H), 1.82-1.72 (m, 1H), 0.79-0.73 (m, 4H). HPLC-MS (ESI+): m/z 458.2[30%, (M+H)⁺], 229.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 458.3 [100%,(M+H)⁺], 229.6 [10%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₁N₇O(M+H) 458.2663, found 458.2647.

5-Methyl-N⁴-(3-[3-(methylethyl)ureido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA2-082-2)

Dry THF (1.5 mL) was added to an oven-dried reaction tube 5 mL Acepressure tube. Argon was bubbled through the solvent for 15 min andPdCl₂(dppf) (10.6 mg, 0.1 eq.) and 4-(4-methylpiperazino)aniline (24 mg)were added sequentially. The mixture was then stirred at roomtemperature for about 2 minutes. Finally, the 2-chloropyrimidineMA2-058-2 (40 mg) and KO^(t)Bu (32 mg, 2.4 eq.) were added. The pressuretube was heated in a oil bath (100° C.) and stirred for 11 h. Thereaction mixture was filtered through a pad of celite and purified bychromatography eluting with MeOH-DCM to provide the title compound as ayellow solid (32 mg, 54%). Mp: 268° C. (dec). HPLC: 98% [t_(R)=5.0 min,40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d):δ 8.68 (s, 1H, 60% reduced on D₂O shake), 8.30 (s, 1H, 20% reduced onD₂O shake), 8.18 (s, 1H, 55% reduced on D₂O shake), 7.81 (s, 1H), 7.60(s, 1H), 7.51 (d, J=9.0 Hz, 2H), 7.21 (s, 1H), 7.17-7.11 (m, 2H), 6.74(d, J=9.0 Hz, 2H), 6.08 (d, J=7.3 Hz, 1H, 85% reduced on D₂O shake),3.73 (m, 1H), 3.02-2.96 (m, 4H), 2.46-2.39 (m, 4H), 2.21 (s, 3H), 2.07(s, 3H), 1.08 (d, J=6.5 Hz, 6H). HPLC-MS (ESI+): m/z 475.3 [30%,(M+H)⁺], 238.2 [100%, (M+H)²⁺]. LC-MS (ESI+): 475.3 [100%, (M+H)⁺]. HRMS(ESI+): m/z calcd for C₂₆H₃₄N₈O (M+H)⁺ 475.2928, found 475.2910.

N⁴-(3-[(1-Methylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]quinazoline-2,4-diamine(MA2-085)

This was obtained as a yellow solid (59 mg, 41%) from MA2-084 (50 mg)and 4-(4-methylpiperazino)aniline (25 mg) using the general method x.Mp: 225° C. (dec). HPLC: 100% [t_(R)=7.0 min, 45% MeOH, 55% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.78 (s, 1H,disappeared on D₂O shake), 8.94 (s, 1H, disappeared on D₂O shake), 8.49(brd, J=7.6 Hz, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.25 (brs, 1H), 7.77-7.62(m, 4H; 1H disappeared on D₂O shake), 7.58 (t, J=7.6 Hz, 1H), 7.53 (d,J=7.6 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 6.88 (d,J=9.0 Hz, 2H), 3.27 (septet, J=6.6 Hz, 1H), 3.11-3.00 (m, 4H), 2.48-2.42(m, 4H), 2.22 (s, 3H), 1.00 (d, J=6.6 Hz, 6H). HPLC-MS (ESI+): m/z 532.2[50%, (M+H)⁻], 266.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 532.2 [100%,(M+H)⁺], 266.6 [50%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₃N₇O₂S(M+H)⁺ 532.2489, found 532.2478.

5-Carboxy-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-086-01)

To a solution of RJ1-066-01 (40 mg, 0.070 mmol) in THF/H₂O (1.5:1, 2.5mL) was added 1 M NaOH solution (0.140 mL). The mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure and the crude paste was purified via HPLC elutingwith 55% MeOH and 45% water (with 0.1% TFA) to provide the titlecompound as a yellow solid (12 mg, 32%). Mp: 199° C. (dec). HPLC: 88%[t_(R)=6.7 min, 45% MeOH, 55% water (with 0.1% TFA), 20 min]. ¹H NMR at80° C. (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.39 (s, 1H), 8.69 (s, 1H),8.05 (d, J=7.7 Hz, 1H), 7.92 (s, 1H), 7.59-7.44 (m, 4H), 7.22 (s, 1H),6.94 (d, J=9.0 Hz, 2H), 3.40-3.25 (m, 4H, partly overlapped by watersignal), 2.50-2.45 (m, 4H, overlapped by residual DMSO solvent signal),2.86 (s, 3H), 1.13 (s, 9H). HPLC-MS (ESI+): m/z 270.7 [100%, (M+2H)²⁺],540.3 [20%, (M+H)⁺]. LC-MS (ESI+): 540.2 [100%, (M+H)⁺]. HRMS (ESI+):m/z calcd for C₂₆H₃₃N₇O₄S (M+H)⁺ 540.2388, found 540.2406.

5-Carboxy-N⁴-(4-chloro-3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-102)

To a solution of RJ1-064-01 (40 mg, 0.080 mmol) in THF/H₂O (1.5:1, 2.5mL) was added 1 M NaOH solution (0.480 mL). The mixture was stirred for29 h at 50° C. The solvent was removed, water (1 mL) was added, and themixture acidified to pH 2 by addition of 1 M HCl. The mixture wasconcentrated under reduced pressure to provide the product as a lightyellow solid (74 mg). Mp: 219° C. (dec). HPLC: 99% [t_(R)=6.7 min, 45%MeOH, 55% water (with 0.1% TFA), 20 min]. ¹H NMR at 80° C. (400 MHz,DMSO-d₆): δ 10.43 (s, 1H, disappeared on D₂O shake), 9.41 (s, 1H,disappeared on D₂O shake), 8.66 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.39(s, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 6.90 (d, J=9.0Hz, 2H), 3.72 (s, 3H), 3.18-3.12 (m, 4H, overlapped by water signal),2.50-2.46 (m, 4H, overlapped by residual DMSO solvent signal), 2.83 (s,3H). HPLC-MS (ESI+): m/z 469.3 [50%, (M³⁵Cl+H)⁺], 236.2 [40%,(M³⁷Cl+2H)²⁺], 235.2 [100%, (M³⁵Cl+2H)²⁺]. LCMS (ESI+): 471.2 [30%,(M³⁷Cl+H)⁺]. 469.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₃H₂₅ClN₆O₃ (M+H)⁺ 469.1794, found 469.1741.

N⁴-(4-Methyl-[3-(N-1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]quinazoline-2,4-diamine(SG2-120)

This was obtained as a yellow solid (30 mg, 43%) from SG2-115 (50 mg)and 4-(4-methylpiperazino)aniline (24 mg) using the general method x.Mp: 241° C. (dec). HPLC: 99% [t_(R)=6.7 min, 50% MeOH, 50% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.69 (s, 1H,disappeared on D₂O shake), 8.88 (s, 1H, disappeared on D₂O shake), 8.36(d, J=8.1 Hz, 1H), 8.32 (br d, J=8.6 Hz, 1H), 8.28 (br s, 1H), 7.66 (brd, J=9.1 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.55 (s, 1H, disappeared onD₂O shake), 7.41 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.22 (t,J=7.6 Hz, 1H), 6.86 (d, J=9.1 Hz, 2H), 3.08-3.01 (m, 4H), 2.57 (s, 3H),2.46-2.41 (m, 4H), 2.20 (s, 3H), 1.13 (s, 9H). HPLC-MS (ESI+): m/z 560.2[20%, (M+H)⁺], 280.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 560.3 [100%,(M+H)⁺], 280.6 [30%, (M+2H)²⁺], 252.6 [60%, (M+2H-tBu)²⁺]. HRMS (ESI+):m/z calcd for C₃₀H₃₇N₇O₂S (M+H)⁺ 560.2802, found 560.2784.

5-Methyl-N⁴-(4-methyl-[3-(N-1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-121)

This was obtained as a red solid (25 mg, 32%) from SG2-108 (52 mg) and4-(4-methylpiperazino)aniline (27 mg) using the general method x. Mp:268° C. (dec). HPLC: 98% [t_(R)=11.4 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 1H, disappeared onD₂O shake), 8.44 (s, 1H, disappeared on D₂O shake), 8.11 (d, J=1.9 Hz,1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 7.83 (s, 1H), 7.47 (s, 1H,disappeared on D₂O shake), 7.44 (d, J=9.1 Hz, 2H), 7.25 (d, J=8.2 Hz,1H), 6.78 (d, J=9.1 Hz, 2H), 3.04-2.96 (m, 4H), 2.54 (s, 3H), 2.45-2.38(m, 4H), 2.19 (s, 3H), 2.07 (s, 3H), 1.09 (s, 9H). HPLC-MS (ESI+): m/z524.2 [20%, (M+H)⁺], 262.8 [100%, (M+2H)²⁺]. LC-MS (ESI+): 524.3 [100%,(M+H)⁺], 262.6 [10%, (M+2H)²⁺], 234.6 [40%, (M+2H-tBu)²⁺]. HRMS (ESI+):m/z calcd for C₂₇H₃₇NO₂S (M+H)⁺ 524.2802, found 524.2809.

5-Carbamoyl-N⁴-(4-chloro-3-methoxyphenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-135)

This was obtained as a brown thin film (14 mg, 20%) from SG2-132 (48 mg)and 4-(4-methylpiperazino)aniline (29 mg) using the general method x.Mp: 242° C. (dec). HPLC: 86% [t_(R)=7.8 min, 30% MeOH, 70% water (with0.1% TFA), 20 min]. ¹H NMR at 80° C. (400 MHz, DMSO-d₆): δ 11.45 (s, 1H,disappeared on D₂O shake), 9.07 (s, 1H, disappeared on D₂O shake), 8.65(s, 1H), 7.46-7.33 (m, 5H; 2H disappeared on D₂O shake), 7.28-7.15 (m,2H), 6.83 (d, J=9.0 Hz, 2H), 3.70 (s, 3H), 3.12-3.01 (m, 4H, overlappedby water signal, but partly visible upon D₂O shake), 2.50-2.45 (m, 4H,overlapped by residual DMSO solvent signal), 2.24 (s, 3H). HPLC-MS(ESI+): m/z 468.3 [40%, (M³⁵Cl+H)⁺], 235.8 [40%, (M³⁷Cl+2H)²⁺], 234.7[100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 470.2 [30%, (M^(5S)Cl+H)⁺], 468.2[100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₃H₂₆ClN₇₀₂ (M+H)⁺468.1909, found 468.1913.

5-Carbamoyl-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-142-01)

This was obtained as a yellow solid (14 mg, 20%) from SG2-139-01 (50 mg)and 4-(4-methylpiperazino)aniline (25 mg) using the general method x.Mp: 200° C. (dec). HPLC: 92% [t_(R)=11.4 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR at 80° C. (400 MHz, DMSO-d₆): δ 11.65 (s, 1H,disappeared on D₂O shake), 9.09 (s, 1H, disappeared on D₂O shake), 8.68(s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.88 (s, 1H), 7.54-7.41 (m, 6H; 2Hdisappeared on D₂O shake), 7.22 (s, 1H, disappeared on D₂O shake), 6.87(d, J=9.0 Hz, 2H), 3.13-3.07 (m, 4H, partly overlapped by water signal),2.50-2.45 (m, 4H, overlapped by residual DMSO solvent signal), 2.24 (s,3H), 1.13 (s, 9H). HPLC-MS (ESI+): m/z 539.2 [50%, (M+H)⁺], 270.2 [100%,(M+2H)²⁺]. LC-MS (ESI+): 539.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₆H₃₄N₈O₃S (M+H)⁺ 539.2547, found 539.2545.

N⁴-(3-[N-(1,1-Dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(MA3-006-1)

This was obtained as a white solid (13 mg, 19%) from MA2-098-1 (50 mg)and 4-(4-methylpiperazino)aniline (25 mg) using the general method x.Mp: 281° C. (dec). HPLC: 98% [t_(R)=19.5 min, 40% MeOH, 60% water (with0.1% TFA), 40 min]. ¹H NMR (400 MHz, DMSO-d): δ 8.78 (s, 1H, disappearedon D₂O shake), 8.76 (s, 1H, disappeared on D₂O shake), 8.19 (d, J=7.1Hz, 1H), 8.11 (brs, 1H), 7.56 (brs, 1H, disappeared on D₂O shake), 7.49(d, J=9.0 Hz, 2H), 7.46-7.39 (m, 2H), 6.82 (d, J=9.0 Hz, 2H), 3.05-2.98(m, 4H), 2.75 (t, J=7.7 Hz, 2H), 2.70 (t, J=7.7 Hz, 2H), 2.47-2.42 (m4H), 2.21 (s, 3H), 2.00 (quint, J=7.7 Hz, 2H), 1.10 (s, 9H). HPLC-MS(ESI+): m/z 536.3 [30%, (M+H)⁻], 268.7 [100%, (M+2H)²⁺]. LC-MS (ESI+):536.3 [100%, (M+H)⁺], 268.7 [15%, (M+2H)²⁺], 240.6 [40%,(M-^(t)Bu+3H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₇N₇O₂S (M+H) 536.2802,found 536.2798.

N⁴-(3-[N-(1-Methylethyl)sulfamoyl]phenyl)-N₂-[4-(4-methylpiperazin-1-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(MA3-006-2)

This was obtained as a white solid (19 mg, 27%) from MA2-098-2 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 223° C. (dec). HPLC: 98% [t_(R)=10.9 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.79 (s 1H, disappearedon D₂O shake), 8.76 (s 1H, disappeared on D₂O shake), 8.28 (d, J=7.9 Hz,1H), 8.04 (s, 1H), 7.61 (d, J=6.5 Hz, 1H, disappeared on D₂O shake),7.50 (d, J=9.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H),6.83 (d, J=9.0 Hz, 2H), 3.23 (oct, J=6.5 Hz, 1H), 3.06-2.97 (m, 4H),2.76 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.46-2.42 (m, 4H), 2.22(s, 3H), 2.01 (quint, J=7.5 Hz, 2H), 0.97 (d, J=6.5 Hz, 6H). HPLC-MS(ESI+): m/z 522.3 [30%, (M+H)⁺], 261.7 [100%, (M+2H)²⁻]. LC-MS (ESI+):522.3 [100%, (M+H)⁺], 261.6 [30%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₇H₃₅N₇O₂S (M+H)⁺ 522.2646, found 522.2627.

N⁴-(3-[N-Cyclopropylsulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(MA3-006-3)

This was obtained as off white solid (21 mg, 29%) from MA2-098-3 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 227° C. (dec). HPLC: 99% [t_(R)=7.6 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.85 (s, 1H,disappeared on D₂O shake), 8.79 (s, 1H, disappeared on D₂O shake), 8.38(d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.93 (brs, 1H disappeared on D₂Oshake), 7.51 (d, J=8.0 Hz) overlapping 7.49 (d, J=9.0 Hz, 2H), 7.40 (d,J=7.8 Hz, 1H), 6.83 (d, J=9.1 Hz, 2H), 3.06-3.00 (m, 4H), 2.77 (t, J=7.3Hz, 2H), 2.72 (t, J=7.3 Hz, 2H), 2.48-2.41 (m, 4H), 2.21 (s, 3H), 2.15(m, 1H), 2.07-1.96 (quintet, J=7.3 Hz, 2H), 0.54-0.45 (m, 2H), 0.44-0.38(m, 2H). HPLC-MS (ESI+): m/z 520.3 [30%, (M+H)⁺], 260.7 [100%,(M+2H)²⁺]. LC-MS (ESI+): 520.2 [100%, (M+H)⁺], 260.6 [35%, (M+2H)²⁺].HRMS (ESI+): m/z calcd for C₂₇H₃₃N₇O₂S (M+H)⁺ 520.2489, found 520.2488.

N⁴-(3-[N-(1-Methylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(MA3-012-2)

This was obtained as a white solid (14 mg, 20%) from MA3-002-2 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 254° C. (dec). HPLC: 97% [t_(R)=5.6 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (s, 1H, 45%reduced on D₂O shake), 8.72 (s, 1H, disappeared on D₂O shake), 8.22-8.18(m, 1H), 7.95 (s, 1H), 7.52-7.44 (m, 4H), 7.34 (d, J=6.9 Hz, 1H,disappeared on D₂O shake), 6.86 (d, J=8.9 Hz, 2H), 4.96 (s, 2H), 4.74(s, 2H), 3.31 (oct, J=6.5 Hz, 1H), 3.16-3.10 (m, 4H, appeared from watersignal on D₂O shake), 2.65-2.52 (m, 4H), 2.33 (s, 3H), 1.01 (d, J=6.5Hz, 6H). HPLC-MS (ESI+): m/z 524.3 [35%, (M+H)⁺], 262.7 [100%,(M+2H)²⁺]. LC-MS (ESI+): 524.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₆H₃₃N₇O₃S (M+H)⁺ 524.2438, found 524.2448.

N⁴-(3-[N-Cyclopropylsulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(MA3-012-3)

This was obtained as off white solid (15 mg, 22%) from MA3-002-3 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 221° C. (dec). HPLC: 95% [t_(R)=7.4 min, 35% MeOH, 65% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, dmso): ¹H NMR (400 MHz, DMSO-d₆) δ10.13 (s, 1H), 9.24 (s, 1H, 70% reduced on D₂O shake), 9.13 (s, 1H,disappeared on D₂O shake), 8.40 (brd, J=8.0 Hz, 1H), 7.97 (d, J=2.5 Hz,1H, disappeared on D₂O shake), 7.90 (s, 1H), 7.55 (d, J=9.1 Hz, 2H),7.51 (d, J=8.0) 7.48-7.41 (m, 1H), 6.93 (d, J=9.1 Hz, 2H), 4.97 (s, 2H),4.76 (s, 2H), 3.69 (s, 2H), 3.48 (s, 2H), 3.16 (s, 2H), 2.95 (s, 2H),2.83 (s, 3H), 2.09-2.13 (m, 1H) 0.52-0.45 (m, 2H), 0.45-0.36 (m, 2H).HPLC-MS (ESI+): m/z 522.3 [65%, (M+H)⁺], 261.8 [100%, (M+2H)²⁺]. LC-MS(ESI+): 522.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₁N₇O₃S(M+H)⁺ 522.2282, found 522.2288.

N⁴-(3-[(1-Methylethyl)sulfonamidophenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(MA3-018)

This was obtained as a white solid (27 mg, 38%) from MA3-016-2 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 258° C. (dec). HPLC: 99% [t_(R)=5.2 min, 35% MeOH, 65% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d): δ 9.74 (s, 1H, disappearedon D₂O shake), 8.94 (s, 1H, disappeared on D₂O shake), 8.89 (s, 1H,disappeared on D₂O shake), 7.69 (d, J=8.0 Hz, 1H), 7.49 (d, J=9.0 Hz,2H), 7.40 (s, 1H), 7.22 (t, J=8.0 Hz, 1H), 6.89 (dd, J=8.0, 1.2 Hz, 1H),6.83 (d, J=9.0 Hz, 2H), 4.93 (s, 2H), 4.73 (s, 2H), 3.25 (septet, J=6.8Hz, 1H), 3.08-2.99 (m, 4H), 2.46-2.40 (m, 4H), 2.21 (s, 3H), 1.24 (d,J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z 524.3 [40%, (M+H)⁺], 262.8 [100%,(M+2H)²⁺]. LC-MS (ESI+): 524.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₆H₃₃N₇O₃S (M+H)⁺ 524.2438, found 524.2435.

N⁴-[3-(Cyclopropylsulfonamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(MA3-022)

This was obtained as a white solid (19 mg, 28%) from MA3-016-3 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 234° C. (dec). HPLC: 93% [t_(R)=14.9 min, 5-95% gradient MeOH-water(with 0.1% TFA), 25 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.19 (s, 1H,disappeared on D₂O shake), 9.03 (s, 1H, disappeared on D₂O shake), 8.43(d, J=7.6 Hz, 1H, disappeared on D₂O shake), 7.96 (d, J=2.2 Hz, 1H),7.88 (s, 1H), 7.56-7.41 (m, 4H), 6.86 (d, J=9.0 Hz, 2H), 4.96 (s, 2H),4.75 (s, 2H), 3.09-3.00 (m, 4H), 2.47-2.41 (m, 4H), 2.21 (s, 3H),2.15-2.07 (m, 1H), 0.52-0.45 (m, 2H), 0.44-0.36 (m, 2H). HPLC-MS (ESI+):m/z 522.2 [40%, (M+H)⁺], 261.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 522.2[100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₁N₇O₃S (M+H) 522.2282,found 522.2298.

N⁴-(3-[(1,1-Dimethylethyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(MA3-023)

This was obtained as a white solid (37 mg, 53%) from MA3-016-1 (50 mg)and 4-(4-methylpiperazino)aniline (25 mg) using the general method x.Mp: 211° C. (dec). HPLC: 98% [t_(R)=7.4 min, 35% MeOH, 65% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.61 (s, 1H,disappeared on D₂O shake), 8.92 (s, 1H, disappeared on D₂O shake), 8.88(s, 1H, disappeared on D₂O shake), 7.68 (d, J=8.0 Hz, 1H), 7.49 (d,J=9.0 Hz, 2H), 7.46 (s, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.01-6.89 (m, 1H),6.83 (d, J=9.0 Hz, 2H), 4.92 (s, 2H), 4.73 (s, 2H), 3.08-2.99 (m, 4H),2.48-2.42 (m, 4H), 2.22 (s, 3H), 1.28 (s, 9H). HPLC-MS (ESI+): m/z 538.3[40%, (M+H)⁺], 269.8 [100%, (M+2H)²⁺]. LC-MS (ESI+): 538.3 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₅N₇O₃S (M+H)⁺ 538.2595, found538.2613.

N⁴-(3-[(1,1-Dimethylethyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(MA3-024-1)

This was obtained as a white solid (9 mg, 13%) from MA3-014-1 (50 mg)and 4-(4-methylpiperazino)aniline (25 mg) using the general method x.Mp: 248° C. (dec). HPLC: 98% [t_(R)=12.8 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.56 (s, 1H,disappeared on D₂O shake), 8.64 (s, 1H, disappeared on D₂O shake), 8.55(s, 1H, disappeared on D₂O shake), 7.62 (d, J=8.1 Hz, 1H), 7.54 (s, 1H),7.51 (d, J=9.0 Hz, 2H), 7.17 (t, J=8.1 Hz, 1H), 6.97-6.90 (m, 1H), 6.81(d, J=9.0 Hz, 2H), 3.05-2.98 (m, 4H), 2.74 (d, J=7.5 Hz, 2H), 2.69 (d,J=7.5 Hz, 2H), 2.47-2.41 (m, 4H), 2.21 (s, 3H), 2.00 (quint, J=7.5 Hz,2H), 1.28 (s, 9H). HPLC-MS (ESI+): m/z 536.4 [40%, (M+H)⁺], 268.7 [100%,(M+1H)²⁺]. LC-MS (ESI+): 536.3 [100%, (M+H)⁺], 208.8 [100%,(M-^(t)Bu+3H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₇N₇O₃S (M+H) 536.2802,found 536.2807.

N⁴-(3-[(1-Methylethyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(MA3-024-2)

This was obtained as off white solid (10 mg, 14%) from MA3-014-2 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 273° C. (dec). HPLC: 99% [t_(R)=7.7 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.68 (s, 1H,disappeared on D₂O shake), 8.64 (s, 1H, disappeared on D₂O shake), 8.56(s, 1H, disappeared on D₂O shake), 7.62 (d, J=8.1 Hz, 1H), 7.51 (d,J=9.0 Hz, 2H), 7.48 (s, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.86 (d, J=8.1 Hz,1H), 6.81 (d, J=9.0 Hz, 2H), 3.24 (septet, J=6.8 Hz, 1H), 3.03 (s, 4H),2.74 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 2.48 (s, 4H, partiallyoverlapped by residual DMSO solvent signal), 2.24 (s, 3H), 2.00(quintet, J=7.4 Hz, 2H), 1.24 (d, J=6.8 Hz, 6H). HPLC-MS (ESI+): HPLC-MS(ESI+): m/z 522.3 [20%, (M+H)⁺], 261.8 [100%, (M+2H)²⁺]. LC-MS (ESI+):522.3 [100%, (M+H)⁺], 261.6 [12%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₇H₃₅N₇O₂S (M+H) 522.2646, found 522.2631.

5-Carbamoyl-N⁴-[3-(cyclopropanesulfonamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-147)

This was obtained as a yellow oil (26 mg, 37%) from SG2-140-01 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.HPLC: 94% [t_(R)=6.7 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min].¹H NMR at 80° C. (400 MHz, DMSO-d₆): δ 11.39 (s, 1H, disappeared on D₂Oshake), 9.38-9.30 (brs, 1H, disappeared on D₂O shake), 8.97 (s, 1H,disappeared on D₂O shake), 8.64 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.46(d, J=9.0 Hz, 2H), 7.42-7.35 (brs, 2H, disappeared on D₂O shake), 7.30(s, 1H), 7.22 (t, 1=8.1 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.85 (d, J=9.0Hz, 2H), 3.13-3.07 (m, 4H), 2.63-2.54 (m, 1H), 2.50-2.45 (m, 4H,overlapped by residual DMSO solvent signal), 2.23 (s, 3H), 1.01-0.87 (m,4H). HPLC-MS (ESI+): m/z 523.2 [40%, (M+H)⁺], 262.3 [100%, (M+2H)²⁺].HPLC-MS (ESI−): m/z 521.1 [100%, (M−H)⁻]. LC-MS (ESI+): 523.2 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₀N₈O₃S (M+H)⁺ 523.2234, found539.2226.

5-Methyl-N⁴-[4-chloro-(3-cyclopropanesulfonamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG2-180)

This was obtained as a light brown solid (29 mg, 41%) from SG2-163 (50mg) and 4-(4-methylpiperazino)aniline (26 mg) using the general methodx. Mp: 202° C. (dec). HPLC: 98% [t_(R)=8.9 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.48-9.38 (brs,1H, disappeared on D₂O shake), 8.64 (s, 1H, disappeared on D₂O shake),8.39 (s, 1H, disappeared on D₂O shake), 7.86 (s, 1H), 7.81 (dd, J=8.8,2.4 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.36 (d,J=8.8 Hz, 1H), 6.81 (d, J=9.0 Hz, 2H), 3.06-2.96 (m, 4H), 2.65-2.56 (m,1H), 2.46-2.40 (m, 4H), 2.20 (s, 3H), 2.07 (s, 3H), 0.96-0.82 (m, 4H).HPLC-MS (ESI+): m/z 528.2 [10%, (M³⁵Cl+H)⁺], 265.7 [50%, (M³⁷Cl+2H)²⁺],264.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 530.2 [30%, (M³⁷Cl+H)⁺], 528.2[100%, (M³⁵Cl+H)⁺], 265.8 [15%, (M³⁷Cl+2H)²⁺], 264.6 [40%,(M³⁵Cl+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₀ClN₇O₂S (M+H)⁺ 528.1943,found 528.1948.

N⁴-[4-chloro-(3-cyclopropanesulfonamido)phenyl]-N⁺-[4-(4-methylpiperazin-1-yl)phenyl]quinazoline-2,4-diamine(SG2-181)

This was obtained as a yellow solid (30 mg, 43%) from SG2-164 (50 mg)and 4-(4-methylpiperazino)aniline (23 mg) using the general method x.Mp: 236° C. (dec). HPLC: 99% [t_(R)=6.5 min, 45% MeOH, 55% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H,disappeared on D₂O shake), 9.49 (brs, 1H, disappeared on D₂O shake),8.80 (s, 1H, disappeared on D₂O shake), 8.33 (d, J=8.0 Hz, 1H), 8.10(brd, J=8.7 Hz, 1H), 7.89 (d, J=2.5 Hz, 1H), 7.70-7.57 (m, 3H), 7.42 (d,J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 1H), 6.87 (d, J=9.0 Hz, 2H), 3.10-3.01(m, 4H), 2.73-2.61 (m, 1H), 2.48-2.43 (m, 4H), 2.21 (s, 3H), 1.01-0.87(m, 4H). HPLC-MS (ESI+): m/z 564.2 [50%, (M³⁵Cl+H)⁺], 283.7 [40%,(M³⁷Cl+2H)²⁺], 282.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 566.2 [40%,(M³⁷Cl+H)⁺], 564.2 [100%, (M³⁵Cl+H)⁺], 283.6 [20%, (M³⁷Cl+2H)²⁺], 282.6[60%, (M³⁵Cl+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₀ClN₇O₂S (M+H)564.1943, found 564.1939.

N⁴-[4-Chloro-3-(cyclopropanesulfonamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(SG2-182)

This was obtained as a brown solid (11 mg, 16%) from SG2-165 (50 mg) and4-(4-methylpiperazino)aniline (24 mg) using the general method x. Mp:192° C. (dec). HPLC: 90% [t_(R)=9.4 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.50-9.40 (brs, 1H,disappeared on D₂O shake), 8.72 (s, 1H, disappeared on D₂O shake), 8.64(s, 1H, disappeared on D₂O shake), 7.91 (dd, J=8.6, 2.5 Hz, 1H), 7.72(d, J=2.5 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.6 Hz, 1H), 6.83(d, J=9.0 Hz, 2H), 3.08-2.97 (m, 4H), 2.74 (t, J=7.4 Hz, 2H), 2.68 (t,J=7.4 Hz, 2H), 2.62-2.54 (m, 1H), 2.46-2.40 (m, 4H), 2.21 (s, 3H), 1.99(quintet, J=7.4 Hz, 2H), 0.95-0.84 (m, 4H). HPLC-MS (ESI+): m/z 554.2[20%, (M³⁵Cl+H)⁺], 278.3 [50%, (M³⁷Cl+2H)²⁺], 277.7 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 574.2 [40%, (M³⁷Cl+H)⁺], 554.2 [100%,(M³⁵Cl+H)⁺], 277.6 [50%, (M³⁵Cl+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₇H₃₂ClN₇O₂S (M+H)⁺ 554.2099, found 554.2094.

N⁴-[4-chloro-3-(cyclopropanesulfonamido)phenyl]-MN-[4-(4-methylpiperazin-1-yl)phenyl]-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(SG2-183)

This was obtained as a brown solid (17 mg, 25%) from SG2-166 (50 mg) and4-(4-methylpiperazino)aniline (24 mg) using the general method x. Mp:190° C. (dec). HPLC: 94% [t_(R)=6.1 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.50-9.35 (brs, 1H,disappeared on D₂O shake), 9.00 (s, 1H, disappeared on D₂O shake), 8.95(s, 1H, disappeared on D₂O shake), 7.94 (brd, J=8.9 Hz, 1H), 7.63 (d,J=2.5 Hz, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.34 (d, J=8.9 Hz, 1H), 6.85 (d,J=9.0 Hz, 2H), 4.93 (s, 2H), 4.72 (s, 2H), 3.09-3.00 (m, 4H), 2.63-2.53(m, 1H), 2.46-2.40 (m, 4H), 2.21 (s, 3H), 0.98-0.81 (m, 4H). HPLC-MS(ESI+): m/z 558.2 [25%, (M³⁷Cl+H)⁺], 556.2 [70%, (M³⁵Cl+H)⁺], 279.4[45%, (M³⁷Cl+2H)²⁺], 278.6 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 558.2[40%, (M³⁵Cl+H)⁺], 556.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₆H₃₀ClN₇O₃S (M+H)⁺ 556.1892, found 556.1900.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-014)

This was obtained as an off-white solid (35 mg, 50%) from SG3-012 (50mg) and 4-(4-methylpiperazino)aniline (25 mg) using the general methodx. Mp: 274° C. (dec). HPLC: 98% [t_(R)=8.4 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.40-9.25 (brs,1H, disappeared on D₂O shake), 8.62 (s, 1H, disappeared on D₂O shake),8.40 (s, 1H, disappeared on D₂O shake), 7.85 (s, 1H), 7.84 (d, J=2.2 Hz,2H), 7.76 (dd, J=8.8, 2.2 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.32 (d,J=8.8 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 3.07-2.96 (m, 4H), 2.46-2.41 (m,4H), 2.20 (s, 3H), 2.07 (s, 3H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z 544.3[20%, (M³⁵Cl+H)⁺], 273.6 [50%, (M³⁷Cl+2H)²⁺], 272.7 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 212.6 [50%, (M³⁵Cl—SO₂tBu+2H)²⁺], 272.6[20%, (M³⁵Cl+2H)²⁺], 544.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₆H₃₄ClN₇O₂S (M+H)⁺ 544.2256, found 544.2242.

5-Fluoro-N⁴-(3-[(1,1-dimethylethyl)sulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA3-066)

This was obtained as a gray solid (45 mg, 62%) from MA3-061 (50 mg) and4-(4-methylpiperazino)aniline (27 mg) using the general method x. Mp:217° C. (dec). HPLC: 99% [t_(R)=6.5 min, 35% MeOH, 65% water (with 0.1%TFA), 20 min]. ¹⁹F NMR (376 MHz, DMSO-d₆): δ −165.02 (s). ¹H NMR (400MHz, DMSO-d₆): δ 9.60 (s, 1H, disappeared on D₂O shake), 9.38 (s, 1H,disappeared on D₂O shake), 8.82 (s, 1H, disappeared on D₂O shake), 8.05(d, J_(HF)=3.7 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.58 (s, 1H), 7.46 (d,J=9.1 Hz, 2H), 7.21 (t, J=8.1 Hz, 1H), 7.01-6.95 (m, 1H), 6.83 (d, J=9.1Hz, 2H), 3.07-3.00 (m, 4H), 2.48-2.41 (m, 4H), 2.21 (s, 3H), 1.28 (s,9H). HPLC-MS (ESI+): m/z 514.3 [80%, (M+H)⁺], 257.7 [100%, (M+2H)²⁺].LCMS (ESI+): 514.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd forC₂₅H₃₂FN₇O₂S (M+H)⁺ 514.2395, found 514.2394.

N⁴-(3-[(1,1-Dimethylethyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]-5,6,7,8-tetrahydroquinazoline-2,4-diamine(MA3-068-1)

This was obtained as off white solid (24 mg, 35%) from MA3-064-1 (50 mg)and 4-(4-methylpiperazino)aniline (24 mg) using the general method x.Mp: 242° C. (dec). HPLC: 100% [t_(R)=6.8 min, 45% MeOH, 55% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.57 (s, 1H,disappeared on D₂O shake), 8.54 (s, 1H, disappeared on D₂O shake), 8.15(s, 1H, disappeared on D₂O shake), 7.52 (s, 1H), 7.49 (d, J=9.0 Hz, 2H),7.44 (d, J=8.1 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H),6.76 (d, J=9.0 Hz, 2H), 3.05-3.00 (m, 4H), 2.57-2.45 (m, 8H, overlappedby residual DMSO solvent signal), 2.29-2.23 (brs, 3H), 1.80-1.72 (m,4H), 1.28 (s, 9H). HPLC-MS (ESI+): m/z 550.3 [20%, (M+H)⁺], 275.8 [100%,(M+2H)²⁺]. LC-MS (ESI+): 550.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₉H₃₉N₇O₃S (M+H)⁺ 550.2959, found 550.2969.

5-Fluoro-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-V-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA3-072)

This was obtained as a white solid (28 mg, 40%) from MA3-070 (50 mg) and4-(4-methylpiperazino)aniline (24 mg) using the general method x. Mp:236° C. (dec). HPLC: 99% [t_(R)=7.1 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹⁹F NMR (376 MHz, DMSO-d₆): δ −164.93 (s). ¹H NMR (400MHz, DMSO-d₆): δ 9.51 (s, 1H, disappeared on D₂O shake), 9.40-9.25 (brs,1H, disappeared on D₂O shake), 8.89 (s, 1H, 80% reduced on D₂O shake),8.08 (d, J=3.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H),7.44 (d, J=9.0 Hz, 2H), 7.36 (d, J=8.8 Hz, 1H), 6.86 (d, J=9.0 Hz, 2H),3.09-3.01 (m, 4H), 2.49-2.40 (m, 4H), 2.22 (s, 3H), 1.31 (s, 9H).HPLC-MS (ESI+): m/z 550.2 [30%, (M³⁷Cl+H)⁺], 548.2 [88%, (M³⁵Cl+H)⁺],275.7 [42%, (M³⁷Cl+2H)²⁺], 274.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+):550.2 [35%, (M³⁷Cl+H)⁺], 548.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₅H₃₁N₇O₃S (M+H)⁺ 548.2005, found 550.2020.

5-Methyl-N⁴-(4-chloro-3,5-dimethoxyphenyl)-M-[4-(1-methylpiperidin-4-ylcarbamoyl)-2-methoxyphenyl]pyrimidine-2,4-diamine(SG3-026-02)

This was obtained as a clear thin film (21 mg, 24%) from SG3-067 (50 mg)and SG3-016 (42 mg) using the general method x, except the mixture washeated in a microwave reactor at 160° C. for 3×15 minutes. HPLC: 97%[t_(R)=7.5 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 8.52 (s, 1H, disappeared on D₂O shake), 8.31 (d,J=8.4 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.98 (s, 1H), 7.67 (s, 1H,disappeared on D₂O shake), 7.45 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.4, 1.7Hz, 1H), 7.22 (s, 2H), 3.90 (s, 3H), 3.85-3.73 (m, 1H), 3.75 (s, 6H),3.05-2.87 (brs, 2H), 2.40-2.28 (brs, 3H), 2.12 (s, 3H), 1.87-1.77 (brd,J=10.9 Hz, 2H), 1.72-1.57 (m, 2H). HPLC-MS (ESI+): m/z 541.3 [10%,(M³⁵Cl+H)⁻], 271.9 [50%, (M³⁷Cl+2H)²⁺], 271.2 [100%, (M³⁵Cl+2H)²⁺].LC-MS (ESI+): 541.2 [100%, (M³⁵Cl+H)⁻], 271.1 [40%, (M³⁵Cl+2H)²⁺]. HRMS(ESI+): m/z calcd for C₂₇H₃₃ClN₆₀₄ (M+H)⁺ 541.2325, found 541.2313.

5-Methyl-N⁴-([3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(1-methylpiperidin-4-ylcarbamoyl)-2-methoxyphenyl]pyrimidine-2,4-diamine(SG3-059)

This was obtained as a white solid (27 mg, 33%) from SG3-053 (50 mg) andSG3-016 (42 mg) using the general method x. Mp: 269° C. (dec). HPLC: 99%[t_(R)=9.3 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.65 (s, 1H, disappeared on D₂O shake), 8.47 (s,1H, disappeared on D₂O shake), 8.40 (d, J=8.6 Hz, 1H), 8.04 (d, J=7.7Hz, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.60 (s, 1H, disappeared on D₂Oshake), 7.43 (s, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H),7.22 (t, J=7.9 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 3.90 (s, 3H), 3.78-3.65(m, 1H), 2.84-2.74 (brd, J=10.3 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H),2.03-1.90 (brt, J=10.7 Hz, 2H), 1.80-1.70 (brd, J=10.7 Hz, 2H),1.64-1.51 (m, 2H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z 582.4 [20%,(M+H)⁻], 291.8 [100%, (M+2H)²⁺]. LC-MS (ESI+): 604.3 [30%, (M+Na)⁺],582.3 [100%, (M+H)⁺], 291.6 [70%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₉H₃₉N₇O₄S (M+H)⁺ 582.2857, found 582.2869.

5-Methyl-N⁴-(4-chloro-3,5-dimethoxyphenyl)-M²-[4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(SG3-064)

This was obtained as an off-white solid (32 mg, 40%) from SG3-067 (50mg) and SG3-051 (37 mg) using the general method x. Mp: 203° C. (dec).HPLC: 95% [t_(R)=12.4 min, 37.5% MeOH, 62.5% water (with 0.1% TFA), 20min]. ¹H NMR at 40° C. (400 MHz, DMSO-d₆): δ 9.18 (s, 1H, disappeared onD₂O shake), 8.34 (s, 1H, reduced by 50% on D₂O shake), 7.96 (s, 1H),7.84 (d, J=7.8 Hz, 1H), 7.72 (d, J=8.9 Hz, 2H), 7.66 (d, J=8.9 Hz, 2H),7.15 (s, 2H), 3.75 (s, 6H), 3.71-3.63 (m, 1H), 2.78-2.70 (brd, J=11.6Hz, 2H), 2.15 (s, 3H), 2.12 (s, 3H), 1.93 (t, J=11.6 Hz, 2H), 1.73 (brd,J=12.3, 3.4 Hz, 2H), 1.56 (qd, J=12.3, 3.4 Hz, 2H). HPLC-MS (ESI+): m/z511.2 [20%, (M³⁵Cl+H)⁺], 257.1 [40%, (M³⁷Cl+2H)²⁺], 256.3 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 513.2 [35%, (M³⁷Cl+H)⁺], 511.2 [100%,(M³⁵Cl+H)], 257.1 [20%, (M³⁷Cl+2H)²⁺]. 256.1 [50%, (M³⁵Cl+2H)²⁺]. HRMS(ESI+): m/z calcd for C₂₆H₃₁ClN₆O₃ (M+H)⁺ 511.2219, found 511.2208.

5-Methyl-N⁴-([3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(SG3-065)

This was obtained as a light brown solid (47 mg, 60%) from SG3-053 (50mg) and SG3-051 (33 mg) using the general method x. Mp: 252° C. (dec).HPLC: 95% [t_(R)=6.8 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.61 (s, 1H, disappeared on D₂O shake),9.16 (s, 1H, reduced by 75% on D₂O shake), 8.45 (s, 1H, reduced by 50%on D₂O shake), 7.92 (s, 1H), 7.91 (brs, 1H), 7.70 (d, J=8.7 Hz, 2H),7.63 (d, J=8.7 Hz, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.47 (s, 1H), 7.23 (t,J=7.9 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 3.75-3.61 (m, 1H), 2.78-2.70 (d,J=10.3 Hz, 2H), 2.13 (s, 3H), 2.09 (s, 3H), 1.90 (t, J=11.7 Hz, 2H),1.75-1.65 (brd, J=10.3 Hz, 2H), 1.54 (qd, J=11.7, 3.5 Hz, 2H), 1.26 (s,9H). HPLC-MS (ESI+): m/z 552.3 [20%, (M+H)⁺], 276.7 [100%, (M+2H)²⁻].HPLC-MS (ESI−): m/z 550.3 [100%, (M−H)⁺]. LC-MS (ESI+): 574.3 [40%,(M+Na)⁺], 552.3 [100%, (M+H)⁺], 276.6 [50%, (M+2H)²⁺]. HRMS (ESI+): m/zcalcd for C₂₈H₃₇N₇O₃S (M+H)⁺ 552.2751, found 552.2759.

5-Methyl-N⁴-([3-(N,N-dimethylsulfamoylamino)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-043A)

This was obtained from SG3-038 (50 mg) and 4-(4-methylpiperazino)aniline(28 mg) using the general method x. The residue was purified via HPLCeluting with gradient 5-95% MeOH and water (with 0.1% TFA) to providethe title compound as a clear thin film (11 mg, 15%). HPLC: 99%[t_(R)=7.6 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹H NMR at80° C. (400 MHz, DMSO-d₆): δ 9.55 (s, 1H, disappeared on D₂O shake),9.17 (brs, 1H, disappeared on D₂O shake), 8.98 (brs, 1H, disappeared onD₂O shake), 7.80 (s, 1H), 7.41-7.31 (m, 4H), 7.24 (t, J=8.0 Hz, 1H),7.04 (d, J=8.0 Hz, 1H), 6.88 (d, J=9.1 Hz, 2H), 3.25-3.10 (m, 4H,overlapped by water signal), 2.86 (s, 3H), 2.72 (s, 6H), 2.49-2.45 (m,4H, overlapped by residual DMSO solvent signal), 2.14 (s, 3H). HPLC-MS(ESI+): m/z 497.3 [20%, (M+H)⁻], 249.2 [100%, (M+2H)²⁺]. LC-MS (ESI+):497.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₄H₃₂N₈O₂S (M+H)⁺497.2442, found 497.2439.

5-Fluoro-N⁴-(phenylbenzamide)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-073)

This was obtained as a yellow solid (29 mg, 40%) from SG3-071 (50 mg)and 4-(4-methylpiperazino)aniline (28 mg) using the general method x.Mp: 240° C. (dec). HPLC: 99% [t_(R)=9.4 min, 35% MeOH, 65% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 10.14 (s, 1H,disappeared on D₂O shake), 9.59 (s, 1H, disappeared on D₂O shake), 9.06(s, 1H, disappeared on D₂O shake), 8.13 (d, J=3.4 Hz, 1H), 8.02 (d,J=8.6 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H), 7.79 (d, J=7.7 Hz, 2H), 7.48 (d,J=8.8 Hz, 2H), 7.35 (t, J=7.7 Hz, 2H), 7.10 (t, J=7.7 Hz, 1H), 6.89 (d,J=8.8 Hz, 2H), 3.11-3.03 (m, 4H), 2.48-2.41 (m, 4H), 2.21 (s, 3H). ¹⁹FNMR (376 MHz, DMSO-d₆): δ −164.70. HPLC-MS (ESI+): m/z 498.3 [80%,(M+H)⁺], 249.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 498.2 [100%, (M+H)⁺].HRMS (ESI+): m/z calcd for C₂₈H₂₈FN₇O (M+H)⁺ 498.2412, found 498.2412.

5-Fluoro-N⁴-(cyclopropylbenzamide)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-081)

This was obtained as a yellow solid (34 mg, 45%) from SG3-076 (50 mg)and 4-(4-methylpiperazino)aniline (31 mg) using the general method x.Mp: 240° C. (dec). HPLC: 99% [t_(R)=5.6 min, 35% MeOH, 65% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.48 (s, 1H,disappeared on D₂O shake), 9.02 (s, 1H, reduced by 35% on D₂O shake),8.33 (d, J=4.1 Hz, 1H), 8.10 (d, J=3.7 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H),7.76 (d, J=8.8 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H),3.09-3.02 (m, 4H), 2.87-2.79 (m, 1H), 2.48-2.42 (m, 4H), 0.73-0.65 (m,2H), 0.58-0.52 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −164.84. HPLC-MS(ESI+): m/z 462.3 [80%, (M+H)⁺], 231.8 [100%, (M+2H)²⁻]. LC-MS (ESI+):462.2 [100%, (M+H)⁻]. HRMS (ESI+): m/z calcd for C₂₅H₂₈FN₇O (M+H)⁺462.2412, found 462.2389.

5-Methyl-N-[3-(1,1-dimethylethylsulfonamido)phenyl]-N²-[4-(1-methylpiperidin-4-yl)phenyl]pyrimidine-2,4-diamine(SG3-082)

This was obtained as a yellow oil (28 mg, 40%) from SG3-053 (50 mg) andSG3-079 (27 mg) using the general method x. HPLC: 98% [t_(R)=15.7 min,35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆):δ 9.61 (s, 1H, disappeared on D₂O shake), 8.75 (s, 1H, disappeared onD₂O shake), 8.35 (s, 1H, disappeared on D₂O shake), 7.87 (s, 1H),7.57-7.52 (m, 3H), 7.48 (d, J=8.1 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H),7.05-6.98 (m, 3H), 2.88-2.81 (brd, J=11.3 Hz, 2H), 2.39-2.26 (m, 1H),2.18 (s, 3H), 2.09 (s, 3H), 1.93 (td, J=12.0, 2.6 Hz, 2H), 1.74-1.53 (m,4H), 1.28 (s, 9H). HPLC-MS (ESI+): m/z 509.3 [20%, (M+H)⁻], 255.2 [100%,(M+2H)²⁺]. LC-MS (ESI+): 531.3 [20%, (M+Na)⁺]. 509.3 [100%, (M+H)⁺],195.1 [50%, (M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₆N₆O₂S(M+H)⁺ 509.2693, found 509.2664.

5-Fluoro-N⁴-(phenylbenzamide)-N²-(4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl)pyrimidine-2,4-diamine (SG3-075)

This was prepared using the reported procedure of Aliagas-Martin, etal., (A class of 2,4-bisanilinopyrimidine Aurora A inhibitors withunusually high selectivity against Aurora B. J Med Chem 2009, 52,3300-7) from SG3-071 (50 mg), 2-(4-aminophenyl)acetic acid (22 mg), TBTU(37 mg), 1-methylpiperazine (10.67 μL), and DIPEA (67 μL) to give thetitle compound as a yellow solid (22 mg, 33%, 3 steps). HPLC: 98%[t_(R)=5.6 min, 45% MeOH, 45% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 10.13 (s, 1H, disappeared on D₂O shake), 9.64 (s,1H, disappeared on D₂O shake), 9.29 (s, 1H, disappeared on D₂O shake),8.17 (d, J=3.4 Hz, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.92 (d, J=8.7 Hz, 2H),7.77 (d, J=7.9 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.33 (t, J=7.9 Hz, 2H),7.13-7.04 (m, 3H), 3.62 (s, 2H), 3.47-3.40 (m, 4H), 2.21-2.12 (m, 4H),2.09 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −163.62. HPLC-MS (ESI+): m/z540.2 [80%, (M+H)⁻], 270.7 [100%, (M+2H)²⁺]. HPLC-MS (ESI−): m/z 538.3[100%, (M−H)⁻]. LC-MS (ESI+): 562.2 [40%, (M+Na)⁺], 540.2 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₃₀H₃₀FN₇O₂ (M+H)⁺ 540.2517, found540.2519.

5-Methyl-N⁴-(cyclopropylbenzamide)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-087-01)

This was obtained as a light yellow solid (35 mg, 47%) from SG3-083 (50mg) and 4-(4-methylpiperazino)aniline (31 mg) using the general methodx. HPLC: 98% [t_(R)=7.7 min, 35% MeOH, 65% water (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.65 (s, 1H, disappeared on D₂Oshake), 8.29 (s, 1H, disappeared on D₂O shake), 8.20 (d, J=3.3 Hz, 1H),7.87 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.45 (d,J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 3.07-3.00 (m, 4H), 2.88-2.78 (m,1H), 2.49-2.43 (m, 4H, overlapped by residual DMSO solvent signal), 2.22(s, 3H), 2.10 (s, 3H), 0.71-0.64 (m, 2H), 0.59-0.52 (m, 2H). HPLC-MS(ESI+): m/z 458.3 [20%, (M+H)⁺], 229.7 [100%, (M+2H)²⁺]. LC-MS (ESI+):458.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₁N₇O (M+H)⁺458.2663, found 458.2667.

5-Methyl-N⁴-(cyclopropylbenzamide)-N²-(4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl)pyrimidine-2,4-diamine(SG3-092)

This was prepared using the reported procedure of Aliagas-Martin et alfrom SG3-083 (50 mg), 2-(4-aminophenyl)acetic acid (25 mg), TBTU (63mg), 1-methylpiperazine (18.30 μL), and DIPEA (115 μL) to give the titlecompound as a light yellow thin film (20 mg, 25%, 3 steps). HPLC: 96%[t_(R)=8.0 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.02 (s, 1H, disappeared on D₂O shake), 8.42 (s,1H, disappeared on D₂O shake), 8.30 (d, J=4.1 Hz, 1H, reduced by 50% onD₂O shake), 7.92 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz,2H), 7.59 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 3.60 (s, 2H),3.46-3.40 (m, 4H), 2.87-2.78 (m, 1H), 2.22-2.17 (m, 2H), 2.17-2.13 (m,2H), 2.11 (s, 6H), 0.71-0.63 (m, 2H), 0.60-0.53 (m, 2H). HPLC-MS (ESI+):m/z 500.3 [20%, (M+H)⁺], 250.8 [100%, (M+2H)²⁺]. HPLC-MS (ESI−): m/z498.3 [100%, (M−H)⁺]. LC-MS (ESI+): 1021.5 [100%, (2M+Na)⁺], 522.2[100%, (M+Na)⁺], 500.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd forC₂₈H₃₃N₇O₂ (M+H)⁺ 500.2768, found 500.2787.

5-Fluoro-N⁴-(cyclopropylbenzamide)-N²-(4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl)pyrimidine-2,4-diamine(SG3-094)

This was prepared using the reported procedure of Aliagas-Martin et al.from SG3-076 (50 mg), 2-(4-aminophenyl)acetic acid (25 mg), TBTU (63mg), 1-methylpiperazine (18.08 μL), and DIPEA (113 μL) to give the titlecompound as a light yellow thin film (20 mg, 25%, 3 steps). HPLC: 96%[t_(R)=7.3 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.54 (s, 1H, disappeared on D₂O shake), 9.25 (s,1H, disappeared on D₂O shake), 8.32 (d, J=3.7 Hz, 1H, reduced by 20% onD₂O shake), 8.14 (d, J=3.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.76 (d,J=8.8 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.6 Hz, 2H), 3.62 (s,2H), 3.47-3.40 (m, 4H), 2.86-2.77 (m, 1H), 2.23-2.14 (m, 4H), 2.11 (s,3H), 0.71-0.64 (m, 2H), 0.59-0.52 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ−163.73. HPLC-MS (ESI+): m/z 504.3 [40%, (M+H)⁻], 252.8 [100%,(M+2H)²⁺]. LC-MS (ESI+): 526.2 [30%, (M+Na)⁺], 504.2 [100%, (M+H)⁺].HRMS (ESI+): m/z calcd for C₂₇H₃₀N₇O₂ (M+H)⁺ 504.2518, found 504.2509.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(1-methylpiperidin-4-yl)phenyl]pyrimidine-2,4-diamine(SG3-111)

This was obtained as an off-white solid (30 mg, 43%) from SG3-012 (50mg) and SG3-079 (24 mg) using the general method x. Mp: 238° C. (dec).HPLC: 97% [t_(R)=11.0 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (s, 1H, disappeared on D₂O shake),8.46 (s, 1H, disappeared on D₂O shake), 7.88 (s, 1H), 7.84 (d, J=2.6 Hz,1H), 7.73 (dd, J=8.8, 2.6 Hz, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.34 (d,J=8.8 Hz, 1H), 7.04 (d, J=8.6 Hz, 2H), 2.93-2.84 (brd, J=11.4 Hz, 2H),2.41-2.30 (m, 1H), 2.22 (s, 3H), 2.08 (s, 3H), 2.07-1.97 (brt, J=11.4Hz, 2H), 1.74-1.55 (m, 4H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z 543.3[20%, (M³⁵Cl+H)⁻], 273.2 [40%, (M³⁷Cl+2H)²⁺], 272.3 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 545.2 [40%, (M³⁷Cl+H)⁺], 543.2 [100%,(M³⁵Cl+H)⁺], 212.1 [50%, (M³⁵Cl—SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcdfor C₂₇H₃₅ClN₆O₂S (M+H)⁺ 543.2304, found 543.2302.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(SG3-112)

This was obtained as an off-white solid (30 mg, 40%) from SG3-012 (50mg) and SG3-051 (30 mg) using the general method x. Mp: 231° C. (dec).HPLC: 97% [t_(R)=8.6 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (s, 1H, disappeared on D₂O shake),8.56 (s, 1H, disappeared on D₂O shake), 7.95 (s, 1H), 7.94 (d, J=8.0 Hz,1H, reduced by 30% on D₂O shake), 7.81 (d, J=2.4 Hz, 1H), 7.78 (dd,J=8.7, 2.4 Hz, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.68 (d, J=9.2 Hz, 2H), 7.38(d, J=8.7 Hz, 1H), 3.77-3.64 (m, 1H), 2.82-2.74 (brd, J=11.5 Hz, 2H),2.17 (s, 3H), 2.11 (s, 3H), 2.03-1.92 (brt, J=11.5 Hz, 2H), 1.73 (dd,J=12.6, 3.4 Hz, 2H), 1.56 (qd, J=12.6, 3.4 Hz, 2H), 1.30 (s, 9H).HPLC-MS (ESI+): m/z 586.3 [25%, (M³⁵Cl+H)⁺], 294.4 [40%, (M³⁷Cl+2H)²⁺],293.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 610.2 [400%, (M³⁷Cl+Na)⁺],608.2 [60%, (M³⁵Cl+Na)⁺], 588.2 [40%, (M³⁷Cl+H)⁺], 586.2 [100%,(M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₆ClN₇O₃S (M+H) 586.2362,found 586.2358.

5-Methyl-N⁴-(4-methyl-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-127)

This was obtained as a light yellow thin film (31 mg, 44%) from SG3-126(50 mg) and 4-(4-methylpiperazino)aniline (26 mg) using the generalmethod x. HPLC: 97% [t_(R)=7.4 min, 40% MeOH, 60% water (with 0.1% TFA),20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (s, 1H, disappeared on D₂Oshake), 8.54 (s, 1H, disappeared on D₂O shake), 8.22 (s, 1H, reduced by50% on D₂O shake), 7.80 (s, 1H), 7.64 (s, 1H), 7.56 (d, J=8.2 Hz, 1H),7.45 (d, J=8.9 Hz, 2H), 7.09 (d, J=8.2 Hz, 1H), 6.77 (d, J=8.9 Hz, 2H),3.06-2.94 (m, 4H), 2.46-2.40 (m, 4H), 2.32 (s, 3H), 2.20 (s, 3H), 2.06(s, 3H), 1.29 (s, 9H). HPLC-MS (ESI+): m/z 524.3 [20%, (M+H)⁺], 262.8[100%, (M+2H)²⁺]. LC-MS (ESI+): 524.3 [100%, (M+H)⁺], 202.6 [40%,(M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₇N₇O₂S (M+H)⁺524.2802, found 524.2813.

5-Methyl-N⁴-([3-phenylsulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-012-1)

This was obtained as a gray solid (21 mg, 30%) from MA4-006-1 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 276° C. (dec). HPLC: 98% [t_(R)=7.4 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): 10.27 (s, 1H, 80% reducedon D₂O shake on D₂O shake), 8.63 (s, 1H, 80% reduced on D₂O shake on D₂Oshake), 8.29 (s, 1H, disappeared on D₂O shake on D₂O shake), 7.82 (s,1H), 7.79-7.77 (m, 2H), 7.62-7.56 (m, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.48(d, J=9.0 Hz, 2H), 7.45-7.41 (m, 3H), 7.12 (t, J=8.0 Hz, 1H), 6.80 (d,J=9.0 Hz, 2H), 6.75 (d, J=7.9 Hz, 1H), 3.10-2.91 (m, 4H), 2.58-2.51 (m,4H, overlapped by the residual DMSO solvent signal) 2.27 (s, 3H, visibleon D₂O shake), 2.06 (s, 3H).). HPLC-MS (ESI+): m/z 530.3 [20%, (M+H)⁻],265.8 [100%, (M+2H)²⁺]. HPLC-MS (ESI−): m/z 528.3 [100%, (M−H)⁻]. LC-MS(ESI+): 552.2 [15%, (M+Na)⁺], 530.2 [100%, (M+H)⁺], 265.6 [5%,(M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₁N₇O₂S (M+H)⁺ 530.2333, found530.2317.

5-Methyl-N⁴-([3-phenylsulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-012-1)

This was obtained as a gray solid (21 mg, 30%) from MA4-006-1 (50 mg)and 4-(4-methylpiperazino)aniline (26 mg) using the general method x.Mp: 276° C. (dec). HPLC: 98% [t_(R)=7.4 min, 40% MeOH, 60% water (with0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): 10.27 (s, 1H, 80% reducedon D₂O shake on D₂O shake), 8.63 (s, 1H, 80% reduced on D₂O shake on D₂Oshake), 8.29 (s, 1H, disappeared on D₂O shake on D₂O shake), 7.82 (s,1H), 7.79-7.77 (m, 2H), 7.62-7.56 (m, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.48(d, J=9.0 Hz, 2H), 7.45-7.41 (m, 3H), 7.12 (t, J=8.0 Hz, 1H), 6.80 (d,J=9.0 Hz, 2H), 6.75 (d, J=7.9 Hz, 1H), 3.10-2.91 (m, 4H), 2.58-2.51 (m,4H, overlapped by the residual DMSO solvent signal) 2.27 (s, 3H, visibleon D₂O shake), 2.06 (s, 3H).). HPLC-MS (ESI+): m/z 530.3 [20%, (M+H)⁻],265.8 [100%, (M+2H)²⁺]. HPLC-MS (ESI−): m/z 528.3 [100%, (M−H)⁻]. LC-MS(ESI+): 552.2 [15%, (M+Na)⁺], 530.2 [100%, (M+H)⁺], 265.6 [5%,(M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₁N₇O₂S (M+H)⁺ 530.2333, found530.2317.

5-Methyl-N⁴-[3-(1,1-dimethylethyl)sulfonamidophenyl]-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(MA4-022-1)

This was obtained as a grayish white solid (31 mg, 42%) from SG3-053 (50mg) and MA4-020 (30 mg) using the general method x. Mp: 233° C. (dec).HPLC: 99% [t_(R)=10.0 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹⁹F NMR (376 MHz, DMSO-d₆): δ −122.41 (dd, J=15.5, 10.1 Hz). ¹H NMR (400MHz, DMSO-d₆): δ 9.61 (s, 1H, disappeared on D₂O shake), 8.93 (s, 1H,80% reduced on D₂O shake), 8.41 (s, 1H, 80% reduced on D₂O shake), 7.88(s, 1H), 7.63 (dd, J=15.6, 2.1 Hz, 1H), 7.50-45 (m, 2H), 7.47 (d, J=2.0Hz, 1H), 7.27-7.19 (m, 2H), 7.03-6.96 (m, 1H), 6.85 (t, J=9.4 Hz, 1H),2.94-2.85 (m, 4H), 2.47-2.41 (m, 4H), 2.21 (s, 3H), 2.09 (s, 3H), 1.27(s, 9H). HPLC-MS (ESI+): m/z 528.3 [40%, (M+H)⁺], m/z 264.8 [100%,(M+2H)²⁺]. LC-MS (ESI+): 528.2 [100%, (M+H)⁺], 204.6 [30%, (M+2H-SO₂^(t)Bu)²⁻]. HRMS (ESI+): m/z calcd for C₂₆H₃₄FN₇O₂S (M+H)⁺ 528.2552,found 528.2560.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(MA4-022-2)

This was obtained as a white solid (35 mg, 49%) from SG3-012 (50 mg) andMA4-020 (27 mg) using the general method x. Mp: 206° C. (dec). HPLC: 97%[t_(R)=10.9 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹⁹F NMR(376 MHz, DMSO-d₆): δ −122.56 (dd, J=14.9, 10.3 Hz). ¹H NMR (400 MHz,DMSO-d₆): δ 9.37 (s, 1H, disappeared on D₂O shake), 8.99 (s, 1H, 90%reduced on D₂O shake), 8.53 (s, 1H, 80% reduced on D₂O shake), 7.91 (s,1H), 7.80-7.76 (m, 2H), 7.62 (d, J=15.9 Hz, 1H), 7.36 (d, J=9.3 Hz, 1H),7.24 (dd, J=8.5, 2.1 Hz, 1H,), 6.89 (t, J=9.3 Hz, 1H), 2.95-2.86 (m,4H), 2.46-2.40 (s, 4H, partially overlapped by residual DMSO solventsignal), 2.22 (s, 3H), 2.10 (s, 3H), 1.31 (s, 9H). HPLC-MS (ESI+): m/z562.3 [40%, (M+H)⁺], m/z 282.7 [100%, (M³⁷Cl+2H)²⁺], m/z 281.7 [50%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): m/z 564.3 [40%, (M³⁷Cl+H)⁺], 562.3 [100%,(M³⁵Cl+H)⁻]. HRMS (ESI+): m/z calcd for C₂₆H₃₃FN₇O₂S (M+H)⁺ 562.2162,found 562.2171.

5-Methyl-N⁴-(3-[(1-methylethyl)sulfonamido]phenyl)-V-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-026)

This was obtained as a green solid (32 mg, 44%) from MA4-008 (50 mg) and4-(4-methylpiperazino)aniline (28 mg) using the general method x. Mp:212° C. (dec). HPLC: 98% [t_(R)=6.6 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.71 (s, 1H, disappeared onD₂O shake), 8.59 (s, 1H, disappeared on D₂O shake), 8.32 (s, 1H,disappeared on D₂O shake), 7.84 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.50(brs, 1H), 7.48 (d, J=9.1 Hz, 2H), 7.23 (t, J=8.6 Hz, 1H), 6.91 (brd,J=8.6 Hz, 1H), 6.79 (d, J=9.1 Hz, 2H), 3.27 (septet, J=6.8 Hz, 1H),3.04-2.97 (m, 4H), 2.47-2.40 (m, 4H), 2.21 (s, 3H), 2.08 (s, 3H), 1.23(d, J=6.8 Hz, 6H). HPLC-MS (ESI+): m/z 496.3 [35%, (M+H)⁺], 248.7 [100%,(M+2H)²⁺]. LC-MS (ESI+): 496.2 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₅H₃₃N₇O₂S (M+H)⁺ 496.2489, found 496.2480.

5-Methyl-N⁴-(4-fluoro-3-[(1,1-dimethylethyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-034)

This was obtained as a white solid (29 mg, 42%) from MA4-025 (50 mg) and4-(4-methylpiperazino)aniline (26 mg) using the general method x. Mp:240° C. (dec). HPLC: 99% [t_(R)=9.5 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹⁹F NMR (376 MHz, DMSO-d₆): δ −129.73 (s). 9.51 (s, 1H,disappeared on D₂O shake), 8.64 (s, 1H, disappeared on D₂O shake), 8.33(s, 1H, disappeared on D₂O shake), 7.84 (d, J=0.7 Hz, 1H), 7.70 (dd,J=7.3, 2.6 Hz, 1H), 7.68-7.63 (m, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.17 (dd,J=10.0, 9.1 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 3.08-2.97 (m, 4H),2.47-2.43 (m, 4H), 2.22 (s, 3H), 2.07 (s, 3H), 1.29 (s, 9H). HPLC-MS(ESI+): m/z 528.3 [20%, (M+H)⁺], 264.7 [100%, (M+2H)²⁺]. LC-MS (ESI+):528.3 [100%, (M+H)⁺], 204.6 [50%, (M+2H-SO₂ ^(t)Bu)²⁺]. HRMS (ESI+): m/zcalcd for C₂₆H₃₄N₇FO₂S (M+H)⁺ 528.2552, found 528.2532.

5-Methyl-N⁴-[3,5-bis-(cyclopropylsulfonamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-084)

This was obtained as a white solid (26 mg, 39%) from MA4-056 (50 mg) and4-(4-methylpiperazino)aniline (21 mg) using the general method x. Mp:265° C. (dec). HPLC: 100% [t_(R)=16.8 min, gradient MeOH-water (with0.1% TFA), 5-95% over 35 min.]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.75 (s,2H, disappeared on D₂O shake), 8.45 (s, 1H, disappeared on D₂O shake),8.42 (s, 1H, disappeared on D₂O shake), 7.86 (s, 1H), 7.47 (d, J=9.1 Hz,2H), 7.29 (brs, 2H), 6.95 (t, J=1.9 Hz, 1H), 6.81 (d, J=9.1 Hz, 2H),3.02-2.95 (m, 4H), 2.61 (ddd, J=12.8, 7.9, 4.8 Hz, 2H), 2.47-2.41 (m,4H, overlapped by residual DMSO solvent signal), 2.24 (s, 3H), 2.07 (s,3H), 1.03-0.96 (m, 4H), 0.96-0.88 (m, 4H). HPLC-MS (ESI+): m/z 613.3[25%, (M+H)⁺], 307.2 [100%, (M+2H)²⁺]. LC-MS (ESI+): 635.2 [20%,(M+Na)⁺], 613.2 [100%, (M+H)⁻], 307.2 [20%, (M+2H)²⁺]. HRMS (ESI+): m/zcalcd for C₂₈H₃₆N₈O₄S₂ (M+H)⁺ 613.2374, found 613.2356.

5-Methyl-N⁴-(4-chloro-3-nitrophenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-155)

A mixture of SG3-149 (450 mg, 1.50 mmol), 4-(4-methylpiperazino)aniline(288 mg, 1.50 mmol), 20 drops of 4 M HCl, and EtOH (9 mL) was heated ina microwave reactor at 160° C. for 15 minutes. The reaction mixture wasdiluted with EtOAc (40 mL). The precipitates were filtered, washed withEtOAc (5 mL, saturated NaHCO₃ (80 mL), and hexanes (80 mL) then driedunder high vacuum to provide the title compound as a green solid (569mg, 83%). Mp: >300° C. HPLC: 99% [t_(R)=7.0 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.86 (s, 1H,disappeared on D₂O shake), 8.68 (s, 1H, disappeared on D₂O shake), 8.53(d, J=2.3 Hz, 1H), 8.11-8.03 (brd, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.61 (d,J=8.9 Hz, 1H), 7.38 (d, J=8.9 Hz, 2H), 6.79 (d, J=8.9 Hz, 2H), 3.05-3.00(m, 4H), 2.46-2.41 (m, 4H), 2.20 (s, 3H), 2.09 (s, 3H). HPLC-MS (ESI+):m/z 454.3 [20%, (M³⁵Cl+H)⁺], 228.7 [40%, (M³⁷Cl+2H)²⁺], 227.7 [100%,(M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 456.2 [300%, (M³⁵Cl+H)⁺], 454.2 [100%,(M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₂H₂₄ClN₇₀₂ (M+H)⁺ 454.1753,found 454.1735.

5-Methyl-N⁴-(4-chloro-3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-158)

This was obtained as a light brown solid (37 mg, 52%) from SG3-145 (50mg) and 4-(4-methylpiperazino)aniline (25 mg) using the general methodx. Mp: 265° C. (dec). HPLC: 97% [t_(R)=7.8 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H,disappeared on D₂O shake), 8.61 (s, 1H, disappeared on D₂O shake), 8.23(d, J=2.5 Hz, 1H, coupling visible upon D₂O shake), 8.22 (brd, J=8.6 Hz,1H, coupling visible upon D₂O shake), 7.88 (s, 1H), 7.65 (s, 1H,disappeared on D₂O shake), 7.45 (d, J=8.6 Hz, 1H), 7.43 (d, J=9.0 Hz,2H), 6.82 (d, J=9.0 Hz, 2H), 3.05-2.99 (m, 4H), 2.46-2.40 (s, 4H), 2.20(s, 3H), 2.08 (s, 3H), 1.12 (s, 9H). HPLC-MS (ESI+): m/z 544.3 [20%,(M³⁵Cl+H)⁺], 273.8 [50%, (M³⁷Cl+2H)²⁺], 272.8 [100%, (M³⁵Cl+2H)²⁺].LC-MS (ESI+): 546.2 [100%, (M³⁷Cl+H)⁻], 544.2 [100%, (M³⁵Cl+H)⁺], 244.6[20%, (M+2H-tBu)²⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₄ClN₇O₂S (M+H)⁺544.2256, found 544.2256.

5-Methyl-N⁴-[4-chloro-(3-propanesulfonamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG3-170)

To a solution of SG3-156 (100 mg, 0.236 mmol) and triethylamine (0.098mL, 0.708 mmol) in pyridine (0.4 mL) was added propane sulfonyl chloride(0.077 mL, 0.650 mmoL). The crude mixture was purified via columnchromatography using DCM/MeOH (0-10%) to provide a mixture of the titlecompound and bis-sulfonylation product (57 mg). The mixture wasdissolved in THF/MeOH (4:1, 1.2 mL) and treated with 1 M NaOH (0.6 mL).The solution was stirred at 50° C. for 2 h. The crude mixture waspurified via preparative TLC using DCM/MeOH 15% and afforded the titleproduct as a light yellow solid (8 mg, 6%). Mp: 208° C. (dec). HPLC: 96%[t_(R)=6.1 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.43 (brs, 1H, disappeared on D₂O shake), 8.66 (s,1H, disappeared on D₂O shake), 8.40 (s, 1H, disappeared on D₂O shake),7.85 (s, 1H), 7.80 (dd, J=8.8, 2.4 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.43(d, J=9.0 Hz, 2H), 7.36 (d, J=8.8 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H),3.10-2.97 (m, 6H), 2.47-2.42 (m, 4H, overlapped by residual DMSO solventsignal), 2.21 (s, 3H), 2.07 (s, 3H), 1.72 (sextet, J=7.5 Hz, 2H), 0.92(t, J=7.5 Hz, 3H). HPLC-MS (ESI+): m/z 530.3 [20%, (M³⁵Cl+H)⁺], 266.7[40%, (M³⁷Cl+2H)²⁺], 265.8 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 532.2[35%, (M³⁷Cl+H)⁺]. 530.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₅H₃₂ClN₇O₂S (M+H)⁺ 530.2099, found 530.2081.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[3-fluoro-4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(SG3-179)

This was obtained as an off-white solid (20 mg, 26%) from SG3-012B3 (50mg) and SG3-153 (32 mg) using the general method x. The resultingmixture was further purified via preparative TLC using DCM/MeOH 15% andafforded the title product as an off-white solid (20 mg, 26%). Mp: 252°C. (dec). HPLC: 98% [t_(R)=9.7 min, 40% MeOH, 60% water (with 0.1% TFA),20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.44 (s, 1H, disappeared on D₂Oshake), 8.63 (s, 1H, disappeared on D₂O shake), 7.97 (s, 1H), 7.82-7.71(m, 4H), 7.41 (t, J=8.6 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.32 (dd,J=8.6, 2.0 Hz, 1H), 3.77-3.65 (brs, 1H), 2.85-2.73 (brs, 2H), 2.22 (s,3H), 2.15-2.07 (brs, 2H), 2.11 (s, 3H), 1.82-1.72 (brd, J=12.5 Hz, 2H),1.61-1.47 (m, 2H), 1.30 (s, 9H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −112.33.HPLC-MS (ESI+): m/z 604.3 [25%, (M³⁵Cl+H)⁺], 303.3 [50%, (M³⁷Cl+2H)²⁺],302.8 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 606.2 [40%, (M³⁷Cl+H)⁺]. 604.2[100%, (M³⁵Cl+H)⁻]. HRMS (ESI+): m/z calcd for C₂₈H₃₅ClFN₇O₃S (M+H)⁺604.2267, found 604.2251.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-M-(4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl)pyrimidine-2,4-diamine(SG3-180)

This was obtained as an off-white solid (25 mg, 33%) from SG3-012B3 (50mg) and SG3-144 (30 mg) using the general method x. Mp: 246° C. (dec).HPLC: 95% [t_(R)=9.6 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.27 (s, 1H, disappeared on D₂O shake),8.82 (s, 1H, disappeared on D₂O shake), 8.45 (s, 1H, disappeared on D₂Oshake), 7.88 (s, 1H), 7.80 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.52 (d,J=8.4 Hz, 2H), 7.31 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 3.57 (s,2H), 3.46-3.38 (m, 4H), 2.22-2.13 (m, 4H), 2.10 (s, 3H), 2.07 (s, 3H),1.29 (s, 9H). HPLC-MS (ESI+): m/z 586.3 [25%, (M³⁵Cl+H)⁺], 294.4 [40%,(M³⁷Cl+2H)^(2+]), 293.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 610.2 [35%,(M³⁷Cl+Na)⁺], 608.2 [100%, (M³⁵Cl+Na)⁺], 588.2 [35%, (M³⁷Cl+H)⁺], 586.2[90%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₆ClN₇O₃S (M+H)⁺586.2362, found 586.2356.

5-Ethoxycarbonyl-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-062)

This was obtained as a white solid (58 mg, 42%) from MA4-048 (100 mg)and 4-(4-methylpiperazino)aniline (46 mg) using the general method x.Mp: 232° C. (dec). HPLC: 99% [t_(R)=7.3 min, 55% MeOH, 45% water (with0.1% TFA), 20 min]. ¹H NMR at 70° C. 10.09 (s, 1H, disappeared on D₂Oshake on D₂O shake), 9.38 (s, 2H, disappeared on D₂O shake on D₂Oshake), 8.69 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H),7.34 (brs, 1H, disappeared on D₂O shake on D₂O shake), 7.23 (t, J=8.1Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.86 (d, J=9.1 Hz, 2H), 4.34 (q, J=7.0Hz, 2H), 3.14-3.09 (m, 4H, overlapped with residual water signals),2.57-2.53 (m, 3H, overlapped by residual DMSO solvent signal), 2.28 (s,3H), 1.35 (t, J=7.0 Hz, 3H), 1.31 (s, 9H). HPLC-MS (ESI+): m/z 568.3[80%, (M+H)⁻], 284.8 [100%, (M+2H)²⁺]. LC-MS (ESI+): 568.3 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₇N₇O₄S (M+H)⁺ 568.2701, found568.2698.

5-Methyl-N⁴-(4-methyl-[3-(N-cyclobutyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-088)

This was obtained as a white solid (36 mg, 51%) from MA4-082 (50 mg) and4-(4-methylpiperazino)aniline (26 mg) using the general method x. Mp:246° C. (dec). HPLC: 100% [t_(R)=7.4 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.71 (s, 1H, 85% reduced onD₂O shake), 8.47 (s, 1H, 85% reduced on D₂O shake on D₂O shake), 8.03(d, J=7.3 Hz, 1H, disappeared on D₂O shake), 8.02 (s, 1H), 7.98 (d,J=8.6 Hz, 1H), 7.85 (d, J=0.7 Hz, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.28 (d,J=8.6 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 3.55 (pentet, J=7.9 Hz, 1H),3.08-2.97 (m, 4H), 2.55 (s, 3H), 2.47-2.39 (m, 4H), 2.22 (s, 3H), 2.09(s, 3H), 1.92-1.76 (m, 4H), 1.49-1.32 (m, 2H). HPLC-MS (ESI+): m/z 522.3[38%, (M+H)⁺], 261.7 [100%, (M+2H)²⁺]. LC-MS (ESI+): 522.3 [100%,(M+H)⁺], 261.6 [30%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₅N₇O₂S(M+H) 5222646, found 522.2643.

5-Methyl-N⁴-(4-methyl-[3-(N-cyclobutyl)sulfamoyl]phenyl)-N₂-[3-fluoro-4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(MA4-089)

This was obtained as a white solid (11 mg, 14%) from MA4-082 (50 mg) andSG3-153 (34 mg) using the general method x. However, reverse phasechromatography (using C₁₈ as the stationary phase and gradient of 5-95%methanol-water as eluent, 35 min) was required to purify the product.Mp: 235° C. (dec). HPLC: 98% [t_(R)=11.7 min, 37.5% MeOH, 62.5% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.47 (s, 1H,disappeared on D₂O shake), 8.67 (s, 1H, disappeared on D₂O shake), 7.96(d, 1H, J=2.3 Hz, in D₂O shake), 7.94 (d, J=2.3 Hz, 1H, in D₂O shake),7.91 (dd, J=8.2, 2.3 Hz, 1H, in D₂O shake), 7.75 (m, 1H, in D₂O shake),7.69 (brs, disappeared on D₂O shake), 7.41 (t, J=8.6 Hz, 1H), 7.35 (d,J=8.2 Hz, 1H, in D₂O shake), 7.32 (dd, J=8.6, 1.9 Hz, 1H, in D₂O shake),3.78-3.69 (m, 1H), 3.55 (sextet, J=8.1 Hz, 1H), 2.70 (brd, J=11.0 Hz,2H), 2.15 (s, 3H), 2.13 (s, 3H), 1.96 (t, J=11.0 Hz, 3H), 1.90-1.74 (m,7H), 1.57-1.35 (m, 6H). HPLC-MS (ESI+): m/z 582.4 [20%, (M+H)⁺], 291.7[100%, (M+2H)²⁺]. LC-MS (ESI+): 604.3 [30%, (M+Na)⁻], 582.3 [100%,(M+H)⁺], 291.6 [15%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₉H₃₆FN₇O₃S(M+H)⁺ 582.2657, found 582.2654.

5-Methyl-N⁴-(4-methyl-[3-(N-cyclobutyl)sulfamoyl]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(MA4-090)

This was obtained as a white solid (46 mg, 63%) from MA4-082 (50 mg) andMA4-020 (28 mg) using the general method x. Mp: 245° C. (dec). HPLC: 99%[t_(R)=8.8 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ. HPLC-MS (ESI+): m/z 540.3 [35%, (M+H)⁺], 279.8[100%, (M+2H)²⁺]. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −122.39 (d, J=11.1 Hz).¹H NMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H, disappeared on D₂O shake),8.55 (s, 1H, disappeared on D₂O shake), 8.02-7.92 (m, 3H, 1H disappearedon D₂O shake), 7.89 (s, 1H), 7.57 (dd, J=15.7, 2.1 Hz, 1H), 7.29 (d,J=8.3 Hz, 1H), 7.23 (dd, J=8.7, 1.9 Hz, 1H), 6.87 (t, J=9.5 Hz, 1H),3.6-3.46 (sextet, J=8.0 Hz, 1H), 2.92-2.85 (m, 4H), 2.54 (s, 3H),2.46-2.39 (m, 4H, overlapped by the residual DMSO solvent signal), 2.19(s, 3H), 2.09 (s, 3H), 1.88-1.74 (m, 4H), 1.47-1.30 (m, 2H). HPLC-MS(ESI+): m/z 540.3 [38%, (M+H)⁺], 270.8 [100%, (M+2H)²⁺]. LC-MS (ESI+):540.3 [100%, (M+H)⁺], 270.6 [25%, (M+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₇H₃₄N₇O₂S (M+H) 540.2552 found 540.2552.

5-Hydroxymethyl-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-NM-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-094)

The ethyl ester MA4-062 (0.047 g) and dry THF (2 mL) were added to anoven dried 10 mL round bottom flask, MA4-062 under an atmosphere ofargon. The mixture was cooled to ice-water temperature and lithiumaluminum hydride (0.331 mL of a 1M solution in THF) was slowly added.The mixture was stirred for 1 h, and additional lithium aluminum hydride(0.497 mL of a 1M solution in THF) was added after which the flask waswarmed to room temperature and stirred for a further 1.5 h. At thisstage TLC and HPLC-MS analysis showed only traces of remaining startingmaterial so the reaction mixture was cooled to −16° C. (using NaCl inice-water) and carefully quenched with cold water (1 mL). Subsequently,the reaction mixture was basified using NaOH (2 mL of 10% aq. solution)and filtered. The resulting residue was partitioned between ethylacetate (50 mL) and water (50 mL). The organic layer was evaporatedunder reduced pressure and the resulting residue purified bychromatography (SiO₂) eluting with using ethyl acetate and hexane toprovide the title compound as a white solid (21 mg, 49%). Mp: 222° C.(dec). HPLC: 99% [t_(R)=7.9 min, 35% MeOH, 65% water (with 0.1% TFA), 20min]. ¹H NMR (400 MHz, DMSO-d₆): 9.59 (s, 1H, disappeared on D₂O shakeon D₂O shake), 8.76 (s, 1H, disappeared on D₂O shake on D₂O shake), 8.35(s, 1H, disappeared on D₂O shake on D₂O shake), 7.92 (s, 1H), 7.60 (d,J=8.3 Hz, 1H), 7.49 (d, J=9.0 Hz, 2H), 7.43 (s, 1H), 7.21 (t, J=8.1 Hz,1H), 6.98 (dd, J=8.1, 2.0 Hz, 1H), 6.82 (d, J=9.0 Hz, 2H), 5.23 (t,J=5.4 Hz, 1H, disappeared on D₂O shake on D₂O shake), 4.46 (d, J=5.4 Hz,2H), 3.10-2.98 (m, 4H), 2.46-2.40 (m, 4H), 2.22 (s, 3H), 1.28 (s, 9H).HPLC-MS (ESI+): m/z 526.3 [20%, (M+H)⁻], 263.8 [100%, (M+2H)²⁺]. LC-MS(ESI+): 548.2 [10%, (M+Na)⁺], 526.3 [100%, (M+H)⁺], 203.2 [10%,(M+2H-SO₂ ^(t)Bu)²⁻]. HRMS (ESI+): m/z calcd for C₂₈H₃₅N₇O₃S (M+H)⁺526.2595, found 526.2585.

5-Methyl-N⁴-(4-methyl-[3-(N-cyclobutyl)sulfamoyl]phenyl)-N²-[4-(1-methylpiperidin-4-yl)phenyl]pyrimidine-2,4-diamine(MA4-100)

This was obtained as a white solid (29 mg, 41%) from MA4-082 (50 mg) andSG3-079 (26 mg) using the general method x. Mp: 219° C. (dec). HPLC:100% [t_(R)=7.1 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹HNMR (400 MHz, DMSO-d₆): 8.90 (s, 1H, 85% reduced on D₂O shake), 8.53 (s,1H, 85% reduced on D₂O shake on D₂O shake), 8.05-7.96 (m, 3H, 1Hdisappeared on D₂O shake), 7.89 (s, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.30(d, J=7.8 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 3.6-3.49 (m, 2H), 2.99 (brd,J=9.1 Hz, 2H), 2.56 (s, 3H), 2.47-2.36 (m, 1H), 2.32 (s, 3H), 2.21-2.15(m, 1H), 2.11 (s, 3H), 1.93-1.59 (m, 8H), 1.49-1.37 (m, 2H). HPLC-MS(ESI+): m/z 521.4 [20%, (M+H)⁺], 261.3 [100%, (M+2H)²⁺]. LC-MS (ESI+):521.3 [100%, (M+H)⁺], 261.1 [25%, (M+2H)^(2i)]. HRMS (ESI+): m/z calcdfor C₂₈H₃₆N₆O₂S (M+H) 521.2693, found 521.2690.

5-Methyl-N⁴-(3-[(1-methylcyclopropyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-102)

This was obtained as a white solid (47 mg, 68%) from MA4-098 (50 mg) and4-(4-methylpiperazino)aniline (26 mg) using the general method x. Mp:222° C. (dec). HPLC: 99% [t_(R)=8.6 min, 35% MeOH, 65% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): 9.72 (s, 1H, disappeared onD₂O shake), 8.56 (s, 1H, disappeared on D₂O shake), 8.32 (s, 1H, 85%reduced on D₂O shake on D₂O shake), 7.84 (s, 1H), 7.60-7.53 (m, 2H),7.48 (d, J=9.1 Hz, 2H), 7.23 (t, J=8.3 Hz, 1H), 6.94 (dd, J=8.0, 1.9 Hz,1H), 6.79 (d, J=9.1 Hz, 2H), 3.06-2.97 (m, 4H), 2.46-2.40 (m, 4H), 2.21(s, 3H), 2.08 (d, J=0.6 Hz, 3H), 1.40 (s, 3H), 1.16-1.10 (m, 2H),0.75-0.68 (m, 2H). HPLC-MS (ESI+): m/z 508.6 [25%, (M+H)⁺], 254.9 [100%,(M+2H)²⁺]. LC-MS (ESI+): 508.3 [100%, (M+H)⁺], 254.6 [10%, (M+2H)²⁺].HRMS (ESI+): m/z calcd for C₂₆H₃₃N₇O₂S (M+H)+508.2489, found 508.2487.

5-Methyl-N⁴-[3-(N-1-methylcyclopropyl)sulfamoyl]phenyl-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(MA4-103)

This was obtained as a white solid (25 mg, 34%) from MA4-098 (50 mg) andMA4-020 (30 mg) using the general method x. The product was purified bycolumn chromatography (SiO₂, eluting with DCM-MeOH, 0-12%) andtriturated from ethanol. Mp: 286° C. (dec). HPLC: 99% [t_(R)=11.9 min,35% MeOH, 65% water (with 0.1% TFA), 20 min]. ¹⁹F NMR (376 MHz,DMSO-d₆): δ −122.39 (dd, J=15.6, 9.5 Hz). ¹H NMR (400 MHz, DMSO-d₆): δ9.74 (s, 1H, disappeared on D₂O shake), 8.90 (s, 1H, disappeared on D₂Oshake), 8.42 (s, 1H, disappeared on D₂O shake), 7.89 (s, 1H), 7.64 (dd,J=15.6, 2.4 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.26 (d,J=8.3 Hz, 1H), 7.23 (t, J=8.6 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 6.85 (t,J=9.8 Hz, 1H), 2.92-2.87 (m, 4H), 2.46-2.39 (m, 4H), 2.21 (s, 3H), 2.10(s, 3H), 1.39 (s, 3H), 1.14-1.10 (m, 2H), 0.73-0.69 (m, 2H). HPLC-MS(ESI+): m/z 526.3 [20%, (M+H)⁺], m/z 263.7 [100%, (M+2H)²⁺]. LC-MS(ESI+): 526.3 [100%, (M+H)⁺], 263.6 [10%, (M+2H)²⁺]. HRMS (ESI+): m/zcalcd for C₂₆H₃₂FN₇O₂S (M+H)⁺ 526.2395, found 526.2401.

5-Methyl-N⁴-[(3-propylsulfonamide)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-108)

A mixture of MA4-106 (60 mg, 0.154 mmol) and dry pyridine (1 mL) in a 5mL round bottom flask was cooled using an ice-bath. 1-Propanesulfonylchloride (22 mg, 0.154 mmol, 17.4 μL) was added via a 20 μL Hamiltonsyringe. After 30 minutes, the ice bath was removed and the mixture wasstirred for an additional 3.5 h at rt. Water (10 mL) was added and themixture was extracted using ethyl acetate (2×15 mL). The organic layerwas dried (Na₂SO₄) and the solvent evaporated. The residue was purifiedvia chromatography (SiO₂, Isolera-4) eluting with a gradient mixture(0-12%) of DCM-MeOH to provide the title compound as a brown solid (24mg, 31%). Mp: 289° C. (dec). HPLC: 97% [t_(R)=7.6 min, 35% MeOH, 65%water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.73 (s,1H, disappeared on D₂O shake), 8.60 (s, 1H, disappeared on D₂O shake),8.31 (s, 1H, disappeared on D₂O shake), 7.84 (d, J=0.8 Hz, 1H), 7.53(dd, J=8.2, 2.2 Hz, 1H), 7.50-7.45 (m, 3H), 7.24 (t, J=8.1 Hz, 1H), 6.89(ddd, J=8.1, 2.1, 0.8 Hz, 1H), 6.79 (d, J=9.1 Hz, 2H), 3.10-3.04 (m,2H), 3.04-2.94 (m, 4H), 2.47-2.40 (m, 4H), 2.22 (s, 3H), 2.08 (s, 3H),1.69 (sextet, J=7.4 Hz 2H), 0.91 (t, J=7.4 Hz, 2H). HPLC-MS (ESI+): m/z496.3 [25%, (M+H)⁺], 248.8 [100%, (M+2H)²⁺]. LC-MS (ESI+): 496.2 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₅H₃₃N₇O₂S (M+H)⁺ 496.2489, found496.2498.

5-Methyl-N⁴-[3-(2-methylpropyl)sulfonamido)phenyl]-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(MA4-116)

This was obtained as a beige solid (24 mg, 30%) from MA4-106 (60 mg) andisobutanesulfonyl chloride (27 mg, 0.17 mmol, 22.1 μL) using the samemethod as described for the synthesis of MA4-108. Mp: 218° C. (dec).HPLC: 99% [t_(R)=6.8 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.73 (s, 1H, disappeared on D₂O shake),8.60 (s, 1H, disappeared on D₂O shake), 8.32 (s, 1H, 85% reduced on D₂Oshake), 7.84 (d, 0.8 Hz, 1H), 7.52 (dd, J=8.1, 1.0 Hz, 1H), 7.50-7.44(m, 3H), 7.25 (t, J=8.1 Hz, 1H), 6.89 (ddd, J=8.1, 2.1, 0.9 Hz, 1H),6.78 (d, J=9.1 Hz, 2H), 3.04-2.99 (m, 4H), 2.98 (d, J=6.6 Hz, 2H),2.47-2.39 (m, 4H), 2.21 (s, 3H), 2.18-2.11 (m, 1H), 2.09 (s, 3H), 0.97(d, J=6.6 Hz, 6H). HPLC-MS (ESI+): m/z 510.3 [25%, (M+H)⁺], 255.8 [100%,(M+2H)²⁺]. LC-MS (ESI+): 510.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcdfor C₂₆H₃₅N₇O₂S (M+H)⁺ 510.2646, found 510.2660.

5-Fluoro-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[3-fluoro-4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(MA4-144-1)

This was prepared from MA3-070B2 (86 mg) and SG3-153 (50 mg) using thegeneral method x.

Purification by column chromatography and crystallization from ethanolgave the title compound as a white solid (27 mg, 22%). Mp: 241° C.(dec). HPLC: 100% [t_(R)=6.3 min, 50% MeOH, 50% water (with 0.1% TFA),20 min]. ¹⁹F NMR (376 MHz, DMSO-d₆): δ −112.31 (dd, J=13.9, 8.3 Hz),−161.95 (s). ¹H NMR (400 MHz, DMSO-d₆): δ 9.72 (s, 1H, disappeared onD₂O shake), 9.67 (s, 1H, disappeared on D₂O shake), 9.36 (s, 1H,disappeared on D₂O shake), 8.22 (d, J=3.6 Hz, 1H), 7.90 (brd, J=7.8 Hz,1H), 7.83 (dd, J=7.4, 2.9 Hz, 1H, 20% reduced on D₂O shake), 7.78 (d,J=2.6 Hz, 1H), 7.76 (dd, J=14.2, 1.8 Hz, 1H), 7.48 (t, J=8.6 Hz, 1H),7.42 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.7, 2.0 Hz, 1H), 3.77-3.63 (m, 1H),2.74 (d, J=13.0 Hz, 2H), 2.18 (s, 3H), 2.06-1.94 (m, 2H), 1.82-1.72 (m,2H), 1.60-1.47 (m, 2H), 1.32 (s, 9H). HPLC-MS (ESI+): m/z 610.3 [30%,(M³⁷Cl+H)⁺], 608.3 [100%, (M³⁵Cl+H)⁻], 305.8 [20%, (M³⁷Cl+2H)²⁺], 304.8[60%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 630.2 [20%, (M+Na)⁺], 610.2 [40%,(M³⁷Cl+H)⁺], 608.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd forC₂₇H₃₂ClF₂N₇O₃S (M+H)⁺ 608.2017, found 608.2008.

5-Fluoro-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(MA4-144-2)

This was obtained as a white solid (34 mg, 42%) from MA3-070B2 (62 mg)and MA4-020 (30 mg) using the general method x. Mp: 244° C. (dec). HPLC:97% [t_(R)=11.8 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹⁹FNMR (376 MHz, DMSO-d₆): δ −122.33 (dd, J=14.7, 10.2 Hz), −163.76 (s). ¹HNMR (400 MHz, DMSO-d₆): δ 9.61 (s, 1H, disappeared on D₂O shake), 9.35(s, 1H, disappeared on D₂O shake), 9.21 (s, 1H, disappeared on D₂Oshake), 8.14 (d, J=3.6 Hz, 1H), 7.94-7.88 (m, 2H), 7.81 (d, J=2.5 Hz,1H), 7.60 (dd, J=15.4, 1.9 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.26 (dd,J=8.7, 1.9 Hz, 1H), 6.94 (t, J=9.8 Hz, 1H), 2.95-2.88 (m, 4H), 2.47-2.42(m, 4H, partially overlapped by residual DMSO signal), 2.22 (s, 3H),1.32 (s, 9H). HPLC-MS (ESI+): m/z 568.3 [30%, (M³⁷Cl+H)⁺], 566.2 [100%,(M³⁵Cl+H)⁺], 284.7 [40%, (M³⁷Cl+2H)²⁺], 283.7 [95%, (M³⁵Cl+2H)²⁺]. LC-MS(ESI+): 568.3 [100%, (M³⁷Cl+H)⁺], 566.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+):m/z calcd for C₂₅H₃₀ClF₂N₇O₂S (M+H)⁺ 566.1911, found 566.1901.

5-Chloro-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[3-fluoro-4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(MA4-146-1)

This was obtained as a white solid (27 mg, 22%) from MA4-142 (69 mg) andSG3-153 (35 mg) using the general method x. Mp: 229° C. (dec). HPLC:100% [t_(R)=10.9 min, 50% MeOH, 50% water (with 0.1% TFA), 20 min]. ¹⁹FNMR (376 MHz, DMSO-d₆): δ −112.29 (dd, J=14.1, 8.4 Hz). ¹H NMR (400 MHz,DMSO-d₆): δ 9.76 (s, 1H, disappeared on D₂O shake), 9.41 (s, 1H,disappeared on D₂O shake), 9.23 (s, 1H, disappeared on D₂O shake), 8.25(s, 1H), 7.82 (dd, J=7.6, 2.5 Hz, 1H, 45% reduced on D₂O shake), 7.73(d, J=2.4 Hz, 1H), 7.66 (dd, J=14.1, 1.0 Hz, 1H), 7.60 (dd, J=8.9, 1.2Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.43 (t, J=8.5 Hz, 1H), 7.34 (dd,J=8.7, 1.7 Hz, 1H), 3.75-3.65 (m, 1H), 2.73 (d, J=10.7 Hz, 2H), 2.18 (s,3H), 2.01 (t, J=9.5 Hz, 2H), 1.76 (dd, J=12.3, 3.3 Hz, 2H), 1.60-1.48(m, 2H), 1.31 (s, 9H). HPLC-MS (ESI+): m/z 626.2 [95%, (M³⁵Cl³⁷Cl+H)⁺],624.2 [100%, (M³⁵Cl³⁵Cl+H)⁺], 313.7 [65%, (M³⁵Cl³⁷Cl+2H)²⁺], 312.7 [85%,(M³⁵Cl³⁵Cl+2H)²⁺]. LC-MS (ESI+): 648.2 [30%, (M³⁷Cl³⁵Cl+Na)⁺], 646.2[35%, (M³⁵Cl³⁵Cl+Na)⁺], 626.2 [70%, (M³⁷Cl³⁵Cl+H)⁺], 624.2 [100%,(M³⁵Cl³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₂C₁₂FN₇O₃S (M+H)624.1721, found 624.1737.

5-Chloro-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(MA4-146-2)

This was prepared from MA4-142 (75 mg) and MA4-020 (35 mg) using thegeneral method x. Purification by chromatography (eluting with MeOH-DCM,0-10%) and crystallization from ethanol gave the title compound as alight brown solid (36 mg, 37%). Mp: 224 (dec). HPLC: 99% [t_(R)=7.4 min,450% MeOH, 55% water (with 0.1% o TFA), 20 min]. ¹⁹F NMR (376 MHz,DMSO-d₆): δ −122.31 (dd, J=14.6, 10.4 Hz), −163.76 (s). ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H, disappeared on D₂O shake), 9.32 (s, 1H, 80%reduced on D₂O shake), 9.10 (s, 1H, 90% reduced on D₂O shake), 8.16 (s,1H), 7.76 (s, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.50 (d, J=16.0 Hz, 1H), 7.40(d, J=8.7 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.88 (t, J=9.5 Hz, 1H),2.96-2.85 (m, 4H), 2.47-2.41 (m, 4H, partially overlapped by residualDMSO signal), 2.22 (s, 3H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z 584.3[70%, (M³⁵Cl³⁷Cl+H)], 582.2 [100% o, (M³⁵Cl³⁵Cl+H)⁺], 292.7 [65%,(M³⁷Cl³⁵Cl+2H)²⁻], 291.7 [45%, (M³⁵Cl³⁵Cl+2H)²⁺]. LC-MS (ESI+): 584.2[70%, (M³⁷Cl³⁵Cl+H)⁺], 582.2 [100%, (M³⁵Cl³⁵Cl+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₅H₃₀C₁₂FN₇₂S (M+H)⁺ 582.1616, found 582.1633.

5-Methyl-N⁴-(4-chloro-[3-(ethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG4-013)

This was obtained as an off-white solid (21 mg, 30%) from SG4-012 (50mg) and 4-(4-methylpiperazino)aniline (26 mg) using the general methodx. Mp: 104-106° C. (dec). HPLC: 98% [t_(R)=7.1 min, 35% MeOH, 65% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.40 (s, 1H,disappeared on D₂O shake), 8.65 (s, 1H, disappeared on D₂O shake), 8.39(s, 1H, disappeared on D₂O shake), 7.85 (s, 1H), 7.81 (d, J=8.6 Hz, 1H),7.67 (d, J=2.4 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.35 (d, J=8.6 Hz, 1H),6.80 (d, J=9.0 Hz, 2H), 3.09 (q, J=7.3 Hz, 2H), 3.05-2.98 (m, 4H),2.45-2.40 (m, 4H), 2.20 (s, 3H), 2.07 (s, 3H), 1.24 (t, J=7.3 Hz, 3H).HPLC-MS (ESI+): m/z 516.3 [15%, (M³⁵Cl+H)⁺], 259.8 [100%, (M³⁷Cl+2H)²⁺],258.8 [35%, (M³⁵Cl+2H)²⁺]. HPLC-MS (ESI−): m/z 514.1 [50%, (M−H)⁻].LC-MS (ESI+): 518.2 [35%, (M³⁷Cl+H)⁺], 516.2 [100%, (M³⁵Cl+H)⁺]. HRMS(ESI+): m/z calcd for C₂₄H₃₀ClN₇O₂S (M+H)⁺ 516.1943, found 516.1961.

5-Methyl-N⁴-(4-chloro-[3-(2-methylpropylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG4-025)

This was obtained as an off-white solid (26 mg, 47%) from SG4-018 (50mg) and 4-(4-methylpiperazino)aniline (19 mg) using the general methodx. Mp: 224° C. (dec). HPLC: 99% [t_(R)=8.9 min, 40% MeOH, 60% water(with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.42 (s, 1H,disappeared on D₂O shake), 8.65 (s, 1H, disappeared on D₂O shake), 8.40(s, 1H, disappeared on D₂O shake), 7.85 (s, 1H), 7.78 (dd, J=8.8, 2.2Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.36 (d, J=8.8Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 3.05-2.99 (m, 4H), 2.96 (d, J=6.6 Hz,2H), 2.46-2.41 (m, 4H), 2.21 (s, 3H), 2.15 (octet, J=6.6 Hz, 1H), 2.07(s, 3H), 0.97 (d, J=6.6 Hz, 6H). HPLC-MS (ESI+): m/z 544.3 [20%,(M³⁵Cl+H)⁺], 273.5 [40%, (M³⁵Cl+2H)²⁺], 272.8 [100%, (M³⁷Cl+2H)²⁺].LC-MS (ESI+): 546.2 [35%, (M³⁷Cl+H)⁺], 544.2 [100%, (M³⁵Cl+H)⁺]. HRMS(ESI+): m/z calcd for C₂₆H₃₄ClN₇O₂S (M+H)⁺ 544.2276, found 544.2256.

5-Methyl-N⁴-(4-chloro-[3-(2-methylpropylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(SG4-027)

This was obtained as a white solid (17 mg, 30%) from SG4-018 (50 mg) andMA4-020 (21 mg) using the general method x. Mp: 222° C. (dec). HPLC: 99%[t_(R)=10.4 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 9.43 (s, 1H, disappeared on D₂O shake), 8.98 (s,1H, disappeared on D₂O shake), 8.50 (s, 1H, disappeared on D₂O shake),7.90 (d, J=0.6 Hz, 1H), 7.75 (dd, J=8.8, 2.3 Hz, 1H), 7.62 (d, J=2.3 Hz,1H), 7.60 (dd, J=15.3, 2.2 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.23 (dd,J=8.6, 2.2 Hz, 1H), 6.87 (dd, J=9.8, 9.1 Hz, 1H), 2.98 (d, J=6.6 Hz,2H), 2.93-2.85 (m, 4H), 2.46-2.38 (m, 4H), 2.20 (s, 3H), 2.15 (octet,J=6.6 Hz, 1H), 2.09 (s, 3H), 0.97 (d, J=6.6 Hz, 6H). ¹⁹F NMR (376 MHz,DMSO-d₆): δ −122.51 (dd, J=15.5, 10.1 Hz). HPLC-MS (ESI+): m/z 562.3[10%, (M³⁵Cl+H)⁺], 282.3 [40%, (M³⁷Cl+2H)²⁺], 281.8 [100%,(M³⁵Cl+2H)²′]. HPLC-MS (ESI−): m/z 560.2 [100%, (M−H)⁻]. LC-MS (ESI+):564.2 [35%, (M³⁷Cl+H)⁺], 562.2 [100%, (M³⁵Cl+H)⁺]. HRMS (ESI+): m/zcalcd for C₂₆H₃₃ClFN₇O₂S (M+H)⁺ 562.2162, found 562.2158.

5-Methyl-N⁴(1-(1,1-dimethylethylsulfonyl)indolin-6-yl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG4-031)

This was obtained as a white solid (36 mg, 52%) from SG4-024 (50 mg) and4-(4-methylpiperazino)aniline (25 mg) using the general method x. Mp:204° C. (dec). HPLC: 98% [t_(R)=10.7 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.53 (s, 1H, disappeared onD₂O shake), 8.25 (s, 1H, disappeared on D₂O shake), 7.79 (s, 1H), 7.47(dd, J=8.1, 1.5 Hz, 1H), 7.45 (d, J=9.1 Hz, 2H), 7.35 (d, J=1.5 Hz, 1H),7.13 (d, J=8.1 Hz, 1H), 6.75 (d, J=9.1 Hz, 2H), 4.04 (t, J=8.4 Hz, 2H),3.08 (t, J=8.4 Hz, 2H), 3.03-2.95 (m, 4H), 2.46-2.40 (m, 4H), 2.20 (s,3H), 2.05 (s, 3H), 1.34 (s, 9H). HPLC-MS (ESI+): m/z 536.3 [10%,(M+H)⁺], 268.8 [100%, (M+2H)²⁺]. LC-MS (ESI+): 558.3 [15%, (M+Na)⁺],536.3 [100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₇N₇O₂S (M+H)⁺536.2802, found 536.2789.

5-Methyl-N⁴(1-(1,1-dimethylethylsulfonyl)indolin-6-yl)-N²-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(SG4-032)

This was obtained as an off-white solid (27 mg, 38%) from SG4-024 (50mg) and MA4-020 (27 mg) using the general method x. Mp: 181-185° C.(dec). HPLC: 98% [t_(R)=11.1 min, 40% MeOH, 60% water (with 0.1% TFA),20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.87 (s, 1H, disappeared on D₂Oshake), 8.35 (s, 1H, disappeared on D₂O shake), 7.84 (s, 1H), 7.60 (dd,J=15.8, 2.3 Hz, 1H), 7.39 (dd, J=8.1, 1.7 Hz, 1H), 7.30 (d, J=1.7 Hz,1H), 7.20 (dd, J=8.7, 1.9 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 6.82 (t,J=9.4 Hz, 2H), 4.04 (t, J=8.4 Hz, 2H), 3.08 (t, J=8.4 Hz, 2H), 2.92-2.84(m, 4H), 2.48-2.41 (m, 4H), 2.20 (s, 3H), 2.07 (s, 3H), 1.33 (s, 9H).¹⁹F NMR (376 MHz, DMSO-d₆): δ −122.65 (dd, J=15.6, 10.1 Hz). HPLC-MS(ESI+): m/z 554.3 [10%, (M+H)⁺], 277.8 [100%, (M+2H)²⁺]. HPLC-MS (ESI−):m/z 552.4 [100%, (M−H)⁻]. LC-MS (ESI+): 554.3 [100%, (M+H)⁺], 217.6[30%, (M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₈H₃₆FN₇O₂S (M+H)⁺554.2708, found 554.2703.

5-Methyl-N⁴(1-(1,1-dimethylethylsulfonyl)indolin-6-yl)-N²-[3-fluoro-4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(SG4-033)

This was obtained as an off-white solid (16 mg, 21%) from SG4-024 (50mg) and SG3-153 (33 mg) using the general method x. Mp: 240° C. (dec).HPLC: 99% [t_(R)=12.1 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.37 (s, 1H, disappeared on D₂O shake),8.48 (s, 1H, disappeared on D₂O shake), 7.91 (d, J=0.8 Hz, 1H), 7.73(dd, J=14.7, 1.9 Hz, 1H), 7.68 (dd, J=7.6, 3.8 Hz, 1H, disappeared onD₂O shake), 7.38 (t, J=8.6 Hz, 1H), 7.34-7.26 (m, 3H), 7.19 (d, J=8.0Hz, 1H), 4.06 (t, J=8.4 Hz, 2H), 3.72-3.60 (m, 1H), 3.10 (t, J=8.4 Hz,2H), 2.68 (d, J=11.3 Hz, 2H), 2.13 (s, 3H), 2.09 (s, 3H), 1.94 (t,J=11.3 Hz, 2H), 1.73 (dd, J=12.4, 3.4 Hz, 2H), 1.50 (qd, J=12.4, 3.4 Hz,2H), 1.32 (s, 9H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −112.31-.-112.43 (m).HPLC-MS (ESI+): m/z 596.3 [10%, (M+H)⁺], 298.7 [100%, (M+2H)²⁺]. LC-MS(ESI+): 618.3 [20%, (M+Na)⁺], 596.3 [100%, (M+H)⁻], 238.1 [35%,(M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcd for C₃₀H₃₈FN₇O₃S (M+H)⁺596.2814, found 596.2811.

5-Methyl-N⁴(1-(1,1-dimethylethylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-N²-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine(SG4-038)

This was obtained as a white solid (22 mg, 32%) from SG4-026 (50 mg) and4-(4-methylpiperazino)aniline (24 mg) using the general method x. Mp:218° C. (dec). HPLC: 97% [t_(R)=11.3 min, 40% MeOH, 60% water (with 0.1%TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.47 (s, 1H, disappeared onD₂O shake), 8.27 (s, 1H, disappeared on D₂O shake), 7.80 (d, J=0.8 Hz,1H), 7.66 (d, J=1.9 Hz, 1H), 7.45 (d, J=9.1 Hz, 2H), 7.28 (dd, J=8.2,1.9 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.74 (d, J=9.1 Hz, 2H), 3.69-3.60(m, 2H), 3.03-2.95 (m, 4H), 2.78 (t, J=6.7 Hz, 2H), 2.45-2.39 (m, 4H),2.19 (s, 3H), 2.05 (s, 3H), 1.94 (quintet, J=6.7 Hz, 2H), 1.32 (s, 9H).HPLC-MS (ESI+): m/z 550.3 [20%, (M+H)⁻], 275.8 [100%, (M+2H)²⁺]. HPLC-MS(ESI−): m/z 548.3 [100%, (M−H)⁻]. LC-MS (ESI+): 550.3 [100%, (M+H)⁺],215.6 [20%, (M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₉H₃₉N₇O₂S(M+H)⁺ 550.2959, found 550.2941.

5-Methyl-N⁴(1-(1,1-dimethylethylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-2M-[4-(4-methylpiperazin-1-yl)-3-fluorophenyl]pyrimidine-2,4-diamine(SG4-039-01)

This was obtained as a yellow foam (21 mg, 29%) from SG4-026 (50 mg) andMA4-020 (26 mg) using the general method x. Mp: 237° C. (dec). HPLC: 96%[t_(R)=12.3 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹H NMR(400 MHz, DMSO-d₆): δ 8.82 (s, 1H, disappeared on D₂O shake), 8.37 (s,1H, disappeared on D₂O shake), 7.84 (d, J=0.7 Hz, 1H), 7.60 (dd, J=15.5,2.1 Hz, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.25 (dd, J=8.2, 2.1 Hz, 1H), 7.21(dd, J=8.4, 1.9 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.81 (dd, J=9.4, 9.1Hz, 1H), 3.68-3.60 (m, 2H), 2.91-2.84 (m, 4H), 2.78 (t, J=6.7 Hz, 2H),2.46-2.38 (m, 4H), 2.19 (s, 3H), 2.07 (s, 3H), 1.94 (quintet, J=6.7 Hz,2H), 1.31 (s, 9H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −122.60 (dd, J=15.3,10.2 Hz). HPLC-MS (ESI+): m/z 568.3 [15%, (M+H)⁺], 284.7 [100%,(M+2H)²⁺]. HPLC-MS (ESI−): m/z 566.2 [100%, (M−H)⁻]. LC-MS (ESI+): 568.3[100%, (M+H)⁺], 224.6 [10%, (M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcd forC₂₉H₃₈FN₇O₂S (M+H) 568.2864, found 568.2867.

5-Methyl-N⁴(1-(1,1-dimethylethylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-N²-[3-fluoro-4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(SG4-043)

A mixture of SG4-026 (50 mg), SG3-153 (32 mg), 3 drops of 4 M HCl, andEtOH (1 mL) in a 2-mL microwave vial was heated in a oil bath at 100° C.for 15 h. Sodium bicarbonate (ca. 100 mg) was added to the mixture,stirred for 30 min at room temperature, and concentrated under reducedpressure. The crude mixture was purified via preparative TLC usingDCM/MeOH 10% and afforded the title product as a light yellow solid (43mg, 56%). Mp: 242° C. (dec). HPLC: 98% [t_(R)=12.6 min, 40% MeOH, 60%water (with 0.1% TFA), 20 min]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (s,1H, disappeared on D₂O shake), 8.50 (s, 1H, disappeared on D₂O shake),7.91 (s, 1H), 7.72 (dd, J=14.8, 1.7 Hz, 1H), 7.70 (brs, 1H), 7.54 (d,J=1.8 Hz, 1H), 7.39 (t, J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 1.7 Hz, 1H),7.23 (dd, J=8.2, 1.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 3.74-3.60 (m, 3H),2.79 (t, J=6.5 Hz, 2H), 2.70 (d, J=11.1 Hz, 2H), 2.15 (s, 3H), 2.09 (s,3H), 2.05-1.90 (m, 4H), 1.73 (dd, J=12.5, 3.8 Hz, 2H), 1.51 (qd, J=12.5,3.8 Hz, 2H), 1.30 (s, 9H). ¹⁹F NMR (376 MHz, DMSO-d₆): δ−112.28-.-112.37 (m) HPLC-MS (ESI+): m/z 610.4 [20%, (M+H)⁺], 305.7[100%, (M+2H)²⁺]. HPLC-MS (ESI−): m/z 608.3 [100%, (M−H)⁻]. LC-MS(ESI+): 632.3 [50%, (M+Na)⁺], 610.3 [100%, (M+H)⁺]. HRMS (ESI+): m/zcalcd for C₃₁H₄₀FN₇O₃S (M+H)⁺ 610.2970, found 610.2966.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-chlorophenyl]pyrimidine-2,4-diamine(SG4-046)

This was obtained from SG3-012 (50 mg) and SG4-030 (29 mg) using thegeneral method y. Further trituration using EtOH/hexanes of the isolatedproduct give the title compound as a light yellow solid (18 mg, 25%).HPLC: 99% [t_(R)=6.4 min, 45% MeOH, 55% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (s, 1H, disappeared on D₂O shake),8.99 (s, 1H, disappeared on D₂O shake), 8.52 (s, 1H, disappeared on D₂Oshake), 7.90 (s, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H),7.71 (d, J=8.9 Hz, 1H), 7.41 (dd, J=8.8, 2.0 Hz, 1H), 7.35 (d, J=8.8 Hz,1H), 7.00 (d, J=8.9 Hz, 1H), 2.91-2.82 (m, 4H), 2.46-2.40 (m, 4H,overlapped by residual DMSO solvent), 2.22 (s, 3H), 2.08 (s, 3H), 1.29(s, 9H). HPLC-MS (ESI+): m/z 578.3 (20%, M³⁵Cl³⁵Cl+H)⁻], 290.7 [80%,(M³⁵Cl³⁷Cl+2H)²⁺], 289.8 [100%, M³⁵Cl³⁵Cl+2H)²⁺]. HPLC-MS (ESI−): m/z578.2 [80%, (M³⁵Cl³⁷Cl—H)⁻], 576.2 [100%, (M³⁵Cl³⁵Cl—H)⁻]. LC-MS (ESI+):580.2 [70%, (M³⁵Cl³⁷Cl+H)⁺], 578.2 [100%, (M³⁵Cl³⁵Cl+H)⁺]. HRMS (ESI+):m/z calcd for C₂₆H₃₃Cl₂N₇O₂S (M−H)⁺ 578.1866, found 578.1847.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-methylphenyl]pyrimidine-2,4-diamine(SG4-047)

This was obtained from SG3-012 (50 mg) and SG4-037 (26 mg) using thegeneral method y. Further trituration using DCM/hexanes of the isolatedproduct give the title compound as an off-white solid (39 mg, 55%).HPLC: 96% [t_(R)=13.2 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (s, 1H, disappeared on D₂O shake),8.69 (s, 1H, disappeared on D₂O shake), 8.45 (s, 1H, disappeared on D₂Oshake), 7.87 (s, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.8, 1.6 Hz,1H), 7.43 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.31 (d, J=8.6 Hz,1H), 6.87 (d, J=8.6 Hz, 1H), 2.79-2.71 (m, 4H), 2.47-2.38 (m, 4H,overlapped by residual DMSO solvent), 2.22 (s, 3H), 2.09 (s, 3H), 2.07(s, 3H), 1.30 (s, 9H). HPLC-MS (ESI+): m/z 558.3 [15%, (M³⁵Cl+H)⁺],280.7 [35%, (M³⁷Cl+2H)²⁺], 279.7 [100%, (M³⁵Cl+2H)²⁺]. HPLC-MS (ESI−):m/z 556.2 [100%, (M³⁵Cl—H)⁺]. LC-MS (ESI+): 560.2 [35%, (M³⁷Cl+H)⁺],558.2 [100%, (M³⁵Cl+H)⁻], 219.6 [40%, (M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/zcalcd for C₂₇H₃₆ClN₇O₂S (M+H) 558.2412, found 558.2412.

5-Methyl-N⁴-[3-(1,1-dimethylethyl)sulfonamidophenyl]-N²-[4-(4-methylpiperazin-1-yl)-3,5-difluorophenyl]pyrimidine-2,4-diamine(MA5-006-1)

This was obtained as a white white solid (31 mg, 42%) from SG3-053 (50mg) and MA4-182-1 (32 mg) using the general method x. Mp: 201° C. (dec).HPLC: 100% [t_(R)=8.3 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹⁹F NMR (376 MHz, DMSO-d₆): δ −119.83 (d, J=12.2 Hz). ¹H NMR (400 MHz,DMSO-d₆): δ 9.62 (s, 1H, disappeared on D₂O shake), 9.20 (s, 1H,disappeared on D₂O shake), 8.49 (s, 1H, 80% reduced on D₂O shake), 7.91(d, J=0.8 Hz, 1H), 7.43 (dd, J=8.0, 1.1 Hz, 1H), 7.40-7.35 (m, 2H), 7.34(brs, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.03 (dd, J=8.0, 1.1 Hz, 1H),3.05-2.95 (m, 4H), 2.46-2.39 (m, 4H), 2.24 (s, 3H), 2.10 (s, 3H), 1.27(s, 9H). HPLC-MS (ESI+): m/z 546.3 [20%, (M+H)⁻], 273.7 [100%,(M+2H)²⁺]. HPLC-MS (ESI−): m/z 544.2 [100%, (M−H)⁻]. LC-MS (ESI+): 546.3[100%, (M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₃F₂N₇O₂S (M+H)⁺546.2457, found 546.2468.

5-Methyl-N⁴-[3-(1,1-dimethylethyl)sulfonamidophenyl]-N₂-[4-(4-methylpiperazin-1-yl)-3-trifluoromethylphenyl]pyrimidine-2,4-diamine(MA5-006-2)

This was obtained as a white solid (31 mg, 38%) from SG3-053 (50 mg) andMA4-182-2 (36 mg) using the general method x. Mp: 208° C. (dec). HPLC:99% [t_(R)=15.5 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹⁹FNMR (376 MHz, DMSO-d₆): δ −59.08 (s). ¹H NMR (400 MHz, DMSO-d₆): δ 9.61(s, 1H, disappeared on D₂O shake), 9.13 (s, 1H, disappeared on D₂Oshake), 8.42 (s, 1H, disappeared on D₂O shake), 7.97 (dd, J=8.8, 2.3 Hz,1H), 7.91 (brs, 2H), 7.52-7.48 (m, 2H), 7.37 (d, J=8.8 Hz, 1H), 7.20 (t,J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 2.87-2.75 (m, 4H), 2.55-2.42 (m,4H, partially overlapped with the residual DMSO signal), 2.26 (brs, 3H),2.11 (s, 3H), 1.27 (s, 9H). HPLC-MS (ESI+): m/z 578.3 [30%, (M+H)⁺],289.8 [100% (M+2H)²⁺]. LC-MS (ESI+): 578.2 [100%, (M+H)⁺]. HRMS (ESI+):m/z calcd for C₂₇H₃₄F₃N₇O₂S (M+H)⁺ 578.2520, found 578.2510.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3,5-difluorophenyl]pyrimidine-2,4-diamine(MA5-008-1)

This was obtained as a beige solid (44 mg, 56%) from SG3-012 (50 mg) andMA4-182-1 (29 mg) using the general method x. Mp: 190° C. (dec). HPLC:100% [t_(R)=6.6 min, 45% MeOH, 55% water (with 0.1% TFA), 20 min]. ¹⁹FNMR (376 MHz, DMSO-d₆): δ −119.89 (d, J=11.8 Hz). ¹H NMR (400 MHz,DMSO-d₆): δ 9.37 (s, 1H, disappeared on D₂O shake), 9.26 (s, 1H,disappeared on D₂O shake), 8.62 (s, 1H, disappeared on D₂O shake), 7.95(s, 1H), 7.73 (dd, J=8.6, 2.1 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.41-7.31(m, 3H), 3.08-2.99 (m, 4H), 2.55-2.45 (m, 4H, overlapped by the residualDMSO signal), 2.27 (brs, 3H), 2.11 (s, 3H), 1.32 (s, 9H). HPLC-MS(ESI+): m/z 581.3 [20%, (M³⁵Cl+H)⁺], 291.4 [40%, (M³⁷Cl+2H)²⁺], 290.7[100%, (M³⁵Cl+2H)²⁺]. HPLC-MS (ESI−): m/z 580.3 [30%, (M³⁷Cl—H)⁻], 578.3[100%, (M³⁵Cl—H)⁻]. LC-MS (ESI+): 582.2 [35%, (M³⁷Cl+H)⁺], 580.2 [100%,(M³⁵Cl+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₂ClF₂N₇O₂S (M+H) 580.2068,found 580.2074.

5-Methyl-N⁴-(4-chloro-[3-(1,1-dimethylethylsulfonamido)]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3-trifluoromethylphenyl]pyrimidine-2,4-diamine(MA5-008-2)

This was obtained as a beige solid (34 mg, 43%) from SG3-012 (50 mg) andMA4-182-2 (33 mg) using the general method x. Mp: 188° C. (dec). HPLC:98% [t_(R)=4.7 min, 50% MeOH, 50% water (with 0.1% TFA), 20 min]. ¹⁹FNMR (376 MHz, DMSO-d₆): δ −59.20 (s). ¹H NMR (400 MHz, DMSO-d₆): δ 9.36(s, 1H, disappeared on D₂O shake), 9.24 (s, 1H, disappeared on D₂Oshake), 8.57 (s, 1H, disappeared on D₂O shake), 7.99 (brs, 1H), 7.95 (s,1H), 7.91 (dd, J=8.8, 2.0 Hz, 1H), 7.83-7.75 (m, 2H), 7.41 (d, J=8.8 Hz,1H), 7.33 (d, J=8.6 Hz, 1H), 2.94-2.88 (m, 4H), 2.68-2.48 (m, 4H,partially overlapped with the residual DMSO signal), 2.46 (s, 3H,completely overlapped by the residual DMSO signal), 2.12 (s, 3H), 1.32(s, 9H). HPLC-MS (ESI+): m/z 614.3 [5%, (M³⁷Cl+H)⁺], 612.3 [20%,(M³⁵Cl+H)⁺], 307.6 [40%, (M³⁷Cl+2H)²⁺], 306.7 [100%, (M³⁵Cl+2H)²⁺].HPLC-MS (ESI−): m/z 612.3 [30%, (M³⁷Cl—H)⁻], 610.3 [100%, (M³⁵Cl—H)].LC-MS (ESI+): 614.2 [35%, (M³⁷Cl+H)⁺], 612.2 [100%, (M³⁵Cl+H)⁻], 246.1[30%, (M-SO₂tBu+2H)²⁺]. HRMS (ESI+): m/z calcd for C₂₇H₃₃ClF₃N₇O₂S(M+H)⁺ 612.2130, found 612.2113.

5-Methyl-N⁴-(4-chloro-3-[(1-methylcyclopropyl)sulfonamido]phenyl)-N²-[4-(4-methylpiperazin-1-yl)-3,5-difluorophenyl]pyrimidine-2,4-diamine(MA5-016-1)

This was obtained as a white solid (26.5 mg, 36%) from MA5-014 (50 mg)and MA4-182-1 (29 mg) using the general method x. Mp: 260° C. (dec).HPLC: 97% [t_(R)=8.0 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min].¹⁹F NMR (376 MHz, DMSO-d₆): δ −119.88 (d, J=12.2 Hz). ¹H NMR (400 MHz,DMSO-d₆): δ 9.51 (s, 1H, disappeared on D₂O shake), 9.25 (s, 1H,disappeared on D₂O shake), 8.61 (s, 1H, disappeared on D₂O shake), 7.95(s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.43-7.32 (m3H), 3.11-2.96 (m, 4H), 2.42-2.37 (m, 4H), 2.20 (s, 3H), 2.11 (s, 3H),1.48 (s, 3H), 1.10-1.06 (m, 2H), 0.77-0.74 (m, 2H). HPLC-MS (ESI+): m/z580.3 [30%, (M³⁷Cl+H)⁺], 578.2 [50%, (M³⁵Cl+H)⁺], 290.7 [40%,(M³⁷Cl+2H)²⁺], 289.7 [100%, (M³⁵Cl+2H)²⁺]. LC-MS (ESI+): 578.2 [100%,(M+H)⁺]. HRMS (ESI+): m/z calcd for C₂₆H₃₀ClF₂N₇O₂S (M+H)⁺ 578.1911,found 578.1938.

5-Methyl-N⁴-(4-chloro-3-[(1-methylcyclopropyl)sulfonamido]phenyl)-N²-[3-fluoro-4-(1-methylpiperidin-4-ylcarbamoyl)phenyl]pyrimidine-2,4-diamine(MA5-018)

This was obtained as a white solid (28 mg, 47%) from MA5-014 (50 mg) andSG3-153 (26 mg) using the general method x. Mp: 191° C. (dec). HPLC: 98%[t_(R)=6.7 min, 40% MeOH, 60% water (with 0.1% TFA), 20 min]. ¹⁹F NMR(376 MHz, DMSO-d₆): δ −112.38 (dd, J=13.6, 8.5 Hz). ¹H NMR (400 MHz,DMSO-d₆): δ 9.61 (brs, 1H, disappeared on D₂O shake), 9.47 (s, 1H,disappeared on D₂O shake), 8.66 (s, 1H, disappeared on D₂O shake), 8.00(d, J=0.7 Hz, 1H), 7.90 (brd, J=7.4 Hz, 1H), 7.80 (dd, J=8.8, 2.6 Hz,1H), 7.78 (dd, J=14.4, 2.0 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.46-7.42(m, 3H), 7.37 (dd, J=8.5, 2.0 Hz, 1H), 3.80-3.79 (m, 1H), 3.05-2.91 (m,2H), 2.50-2.45 (m, 1H), 2.39-2.29 (m, 4H), 2.13 (d, J=0.7 Hz, 3H),1.88-1.81 (m, 2H), 1.69-1.61 (m, 2H), 1.48 (s, 3H), 1.10-1.06 (m, 2H),0.79-0.75 (m, 2H). HPLC-MS (ESI+): m/z 604.2 [10%, (M³⁷Cl+H)⁺], 602.2[40%, (M³⁵Cl+H)⁺], 302.4 [40%, (M³⁷Cl+2H)²⁺], 301.6 [100%,(M³⁵Cl+2H)²⁺]. HPLC-MS (ESI−): m/z 602.3 [35%, (M³⁷Cl—H)⁻], 600.3 [100%,(M³⁵Cl—H)⁻]. LC-MS (ESI+): 624.2 [30%, (M³⁵Cl+Na)⁺], 604.2 [30%,(M³⁷Cl+H)⁺], 602.2 [100%, (M³⁵Cl+H)⁺], 301.6 [20%, (M³⁵Cl+2H)²⁺]. HRMS(ESI+): m/z calcd for C₂₈H₃₃ClFN₇O₃S (M+H)⁺ 602.2111, found 602.2081.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. A compound having FormulaIII:

wherein X is N or CH; L is O, S, C₁₋₄alkyl, C(O)NH, NHC(O), CH₂C(O),C(O)CH₂, CH₂CH₂C(O), CH₂C(O)CH₂, CH₂C(O)NH, NH(CO)CH₂; R¹ is selectedfrom the group consisting of H, Cl, F, Br, I, CN, NO₂, NH₂, CF₃, CO₂H,CO₂NH₂, CO₂NHR⁵, CO₂R⁵, C(O)R⁵, C(O)NH₂, C(O)NHR⁵, or C₁-C₆ alkyloptionally substituted with alkoxy, alkenyl, alkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol; R² isH, OH, CN, NO₂, NH₂, unsubstituted C₁-C₆ alkyl, cycloalkyl, aryl, orheteroaryl; or C₁-C₆ alkyl, cycloalkyl, aryl, or heteroaryl substitutedwith alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol; or R¹ and R² togetherform a fused cycloalkyl, cycloheteroalkyl, aryl or heteraryl group; eachR³ is selected, independently, from the group consisting of SO₂NH₂,SO₂NHR⁵, NHSO₂R⁵, NHCO₂R⁵, NHC(O)R⁵, NHCONHR⁵, F, Cl, Br, I, NO₂, C₁-C₆alkyl, C₁-C₆ alkoxy, cycloheteroaryl, and fused cycloheteroalkyl,optionally substituted with sulfonyl; each R⁵ is selected,independently, from C₁-C₆ alkyl, C₁-C₆ cycloalkyl, aryl, heteroaryl,heterocycloalkyl, or heteroalkyl, any of which are optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxyl, alkenyl, alkynyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide,or thiol; R⁶ is H, C₁-C₆ alkyl, CO₂R⁵, CO₂H, CO₂NHR⁵; R⁷ is H, C₁-C₆alkyl, C₁-C₆ alkoxyl, halide, hydroxyl, cyano, nitro, or amino; R⁸ is OHor ═O; n is 1-5; and p is 1 or 2 or a pharmaceutically acceptable saltthereof.
 5. The compound of claim 4, wherein R¹ is selected from thegroup consisting of Cl, F, Br, I, CF₃, C₁-C₆ alkyl, CN, NO₂, and NH₂;and R² is H, OH, CN, NO₂, NH₂, unsubstituted C₁-C₆ alkyl, cycloalkyl,aryl, or heteroaryl, and C₁-C₆ alkyl, cycloalkyl, aryl, or heteroarylsubstituted with alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde,amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro,silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol.
 6. Thecompound of claim 4, wherein R¹ and R² together form a fused cycloalkyl,cycloheteroalkyl, aryl or heteraryl group.
 7. The compound of claim 4,wherein R¹ and R² together form a fused furan.
 8. The compound of claim4, wherein R¹ and R² together form a fused cyclopentyl or fusedcyclohexyl.
 9. The compound of claim 4, wherein R¹ and R² together forma fused phenyl.
 10. The compound of claim 4, wherein R¹ is C₁₋₈alkyl orheteroalkyl.
 11. The compound of claim 4, wherein R¹ is methyl, ethyl,propyl, butyl, or trifluoromethyl.
 12. The compound of claim 4, whereinR¹ is chloro, bromo, or fluoro.
 13. The compound of claim 4, wherein R¹is CO₂C₁₋₈alkyl, CO₂H, CO₂NH₂, or CO₂NHC₁₋₈alkyl.
 14. The compound ofclaim 4, wherein R² is C₁₋₈ alkyl or heteroalkyl.
 15. The compound ofclaim 4, wherein R² is hydrogen.
 16. The compound of claim 4, wherein nis 1 or
 2. 17. The compound of claim 4, wherein each R³ is selected,independently, from the group consisting of NHSO₂R⁵, NHCO₂R⁵, NHCONHR⁵;wherein R⁵ is C₁-C₆ alkyl, cycloalkyl, heteroalkyl, aryl, or heteroaryl.18. The compound of claim 4, wherein R³ is SO₂NH₂, SO₂NHR⁵, or NHSO₂R⁵,wherein R⁵ is C₁-C₆ alkyl or C₁-C₆ cycloalkyl optionally substitutedwith C₁-C₆ alkyl, C₁-C₆ alkoxyl, hydroxyl, or halide.
 19. The compoundof claim 4, wherein R³ is NHC(O)R⁵, wherein R⁵ is C₁-C₆ alkyl or C₁-C₆cycloalkyl optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxyl,hydroxyl, or halide.
 20. The compound of claim 4, wherein R³ is C₁-C₆alkyl or C₁-C₆ cycloalkyl.
 21. The compound of claim 4, wherein R³ isC₁-C₆ alkoxyl.
 22. The compound of claim 4, wherein R³ is halide. 23.The compound of claim 4, wherein n is 2 and each R³ is selected fromC₁-C₆ alkyl, C₁-C₆ alkoxyl, halide, SO₂NH₂, SO₂NHR⁵, and NHSO₂R⁵,wherein R⁵ is C₁-C₆ alkyl or C₁-C₆ cycloalkyl optionally substitutedwith C₁-C₆ alkyl, C₁-C₆ alkoxyl, hydroxyl, or halide.
 24. The compoundof claim 4, wherein n is 2 and each R³ is selected from C₁-C₆ alkyl,C₁-C₆ alkoxyl, and halide.
 25. The compound of claim 4, wherein n is 3and each R³ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxyl, and halide. 26.The compound of claim 4, wherein n is 2 and each R³ together form afused heterocycloalkyl.
 27. The compound of claim 4, wherein R⁴ ispiperadinyl, piperazinyl, morpholinyl, optionally substituted with C₁₋₆alkyl.
 28. The compound of claim 4, wherein R⁶ is C₁₋₈alkyl.
 29. Thecompound of claim 4, wherein R⁶ is methyl.
 30. The compound of claim 4,wherein R⁶ is hydrogen.
 31. The compound of claim 4, wherein R⁶ ispiperidine,
 32. The compound of claim 4, wherein R⁷ is chloro, bromo, orfluoro.
 33. The compound of claim 4, wherein R⁷ is hydrogen.
 34. Thecompound of claim 4, wherein X is N.
 35. The compound of claim 4,wherein n and m are both
 1. 36. The compound of claim 4, wherein R⁸ isoxo.
 37. (canceled)
 38. The compound of claim 4, wherein the compound ischosen from


39. A pharmaceutical composition comprising the composition of claim 4and a pharmaceutically acceptable carrier.
 40. A method of treatingcancer in a subject comprising, administering to the subject aneffective amount of the composition of claim
 4. 41. The method of claim40, wherein the cancer is selected from the group consisting of bladdercancer, brain cancer, breast cancer, colorectal cancer, cervical cancer,gastrointestinal cancer, genitourinary cancer, head and neck cancer,lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renalcancer, skin cancer, and testicular cancer.
 42. The method of claim 40,further comprising administering a second compound or composition,wherein the second compound or composition includes an anticancer agent.43. A method of killing a tumor cell in a subject, comprising:contacting the tumor cell with an effective amount of the composition ofclaim
 4. 44. The method of claim 43, further comprising contacting thetumor cell with a second compound or composition, wherein the secondcompound or composition includes an anticancer agent.